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- A Tour of the Influence of the Gut Microbiome on Age-Related Conditions
- Hippo Pathway Inhibition Provides Resistance to Ferroptosis in the Aging Brain
- Short Interspersed Nuclear Elements Expression as an Enabler of Nervous System Regeneration
- Valine Restriction Extends Life Span in Male Mice Only
- Reprogramming Research Points to GSTA4 as an Important Component of Many Age-Slowing Interventions
- The Amish as a Point of Comparison for Long-Term Effects of Physical Exercise
- The Role of Bacterial Infection in Atherosclerotic Plaque Rupture
- Neural Progenitor Cell Transplantation Promotes Recovery Following Stroke in Mice
- Iron Metabolism in Osteoporosis
- Failure to Regulate Diastolic Blood Pressure as a Contribution to Cognitive Decline
- Towards Artificial Elastin for Tissue Engineering and Regenerative Medicine
- Betaine as an Exercise Mimetic
- Reviewing the Role of mTOR in Aging
- Resistance Training Improves Peripheral Nerve Function in Older Adults
- Applying Mendelian Randomization to Support a Causal Relationship Between Frailty and Dementia
A Tour of the Influence of the Gut Microbiome on Age-Related Conditions
https://www.fightaging.org/archives/2025/09/a-tour-of-the-influence-of-the-gut-microbiome-on-age-related-conditions/
The evidence of recent years derived from the study of the commensal microbes dwelling in the gastrointestinal tract makes it clear that the composition of this gut microbiome is influential on long term health, likely to a similar degree as exercise and diet. Further, the balance of microbial populations shifts with age in unfavorable ways. Inflammatory populations increase, contributing to the chronic inflammation of aging, while beneficial populations decrease, reducing the supply of metabolites necessary for normal tissue function.
While today's open access paper is ostensibly focused on the connections between gut microbiome and brain, the authors do discuss direct links between age-related changes in the gut microbiome and a range of conditions in the rest of the body, including cardiovascular disease and cancer. All of this lends weight to efforts to restructure the aged gut microbiome, rebalance the distribution of population numbers to youthful levels, and thus reduce its contribution to degenerative aging.
We know that rejuvenation of the gut microbiome is possible and we know that it can last for a long time following a single intervention, as fecal microbiota transplantation from a young donor to an old recipient is fairly well studied in animal models. It does restore a more youthful microbiome, and as a consequence improves health and lengthens life. It will likely be challenging to establish the use of fecal microbiota transpantation more broadly than is presently the case in human medicine, as too many unknowns are involved in a donor microbiome, but there are other options on the table that do not suffer from those issues, such as flagellin immunization or the transplantation of synthetic microbiomes with well-vetted component microbes.
The Brain-Gut-Microbiome Axis Across the Life Continuum and the Role of Microbes in Maintaining the Balance of Health
There is a growing body of evidence that the interaction between various microbial organisms and the human host can affect various physical and even mental health conditions. Bidirectional communication occurs between the brain and the gut microbiome, referred to as the brain-gut-microbiome axis. During aging, changes occur to the gut microbiome due to various events and factors such as the mode of delivery at birth, exposure to medications (e.g., antibiotics), environmental exposures, diet, and host genetics. Connections to the brain-gut-microbiome axis through different systems also change during aging, leading to the development of chronic diseases.
Disruption of the gut microbiome, known as dysbiosis, can lead to a reduction in beneficial bacteria and a corresponding increase in more harmful or even pathogenic bacteria. This imbalance may predispose or contribute to the development of various health conditions and illnesses. Targeted treatment of the gut microbiome and the brain-gut-microbiome axis may assist in the overall management of these various ailments.
The purpose of this review is to describe the changes that occur in the gut microbiome throughout life, and to highlight the risk factors for microbial dysbiosis. We discuss the different health conditions experienced at various stages of life, and how dysbiosis may contribute to the clinical presentation of these diseases. Modulation of the gut microbiome and the brain-gut-microbiome axis may therefore be beneficial in the management of various ailments. This review also explores how various therapeutics may be used to target the gut microbiome. Gut biotics and microbial metabolites such as short chain fatty acids may serve as additional forms of treatment. Overall, the targeting of gut health may be an important strategy in the treatment of different medical conditions, with nutritional modulation of the brain-gut-microbiome axis also representing a novel strategy.
Hippo Pathway Inhibition Provides Resistance to Ferroptosis in the Aging Brain
https://www.fightaging.org/archives/2025/09/hippo-pathway-inhibition-provides-resistance-to-ferroptosis-in-the-aging-brain/
The Hippo pathway shows up in many areas of research into aging, regeneration, cancer, and cellular senescence. This tends to be the case for protein machinery that is involved in cell growth and cell stress responses, including programmed cell death. See the research surrounding nutrient signaling and its relationship with cell growth, centering around mTOR and its surrounding biochemistry, for example. Hippo signaling is fairly complex, but also quite well explored. Nonetheless while individual protein interactions in the pathway are well mapped, how it operates in detail to produce different outcomes in different contexts is less well understood. Its activities regulate both cell proliferation and cell death via apoptosis, both relevant to regeneration, cancer, and aging, among other topics.
In different contexts, researchers have assessed the merits of both inhibition of Hippo signaling to enhance regeneration, suppress cellular senescence and cell death, or encourage the death of cancerous cells. Here, researchers provide evidence for Hippo pathway inhibition to be a path to making the aging brain more resilient to metabolic imbalances that lead to excessive programmed cell death. Ferroptosis is one such cell death pathway, a consequence of dysregulated iron metabolism, and of late shown to be a relevant pathological mechanism in aged tissues. Inducing a lesser degree of ongoing ferroptosis may be protective in the aging brain.
Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis
The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity.
Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis.
These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.
Short Interspersed Nuclear Elements Expression as an Enabler of Nervous System Regeneration
https://www.fightaging.org/archives/2025/09/short-interspersed-nuclear-elements-expression-as-an-enabler-of-nervous-system-regeneration/
Why does the peripheral nervous system regenerate while the central nervous system does not? Both are composed of clusters of neurons linked by axons that can extend for as much as a few feet in the longest cases. Nerves are bundled axons. One of the approaches taken by researchers interested in applying regenerative medicine strategies to the central nervous system is to look for biochemical differences between peripheral nervous system neurons and axons versus central nervous system neurons and axons. There must exist specific differences that enable regeneration of peripheral nervous system axons or suppress regeneration of central nervous system axons. That doesn't mean those differences are easy to find, of course. Biology is exceptionally complex and present omics approaches are not well suited to capturing the full picture of a changing system that is moving through a process over time.
In today's open access paper, researchers report on what they believe to be an important component of peripheral nerve regeneration. Peripheral nervous system neurons express a specific set of short interspersed nuclear elements (SINEs) during axon regrowth, and this does not occur in central nervous system neurons. SINEs are a form of transposable element, repeated DNA sequences capable of copying themselves when activated, and currently a topic of interest for their contribution to degenerative aging when overly active in later life. Transposable elements are largely the remnants of ancient viral infections, but that doesn't rule out the evolution of useful functions for these sequences. Nothing is simple in cellular biochemistry, evolution loves reuse, and few aspects of our biology have only one purpose.
Repeat-element RNAs integrate a neuronal growth circuit
Neuronal growth and regeneration are regulated by RNA localization and local translation. We previously described an intrinsic neuronal-growth-regulating mechanism based on axonal transport of the RNA-binding protein (RBP) nucleolin and local translation of key mRNA cargos, including importin β1 and mTOR. Local translation of these and other mRNAs at the cell periphery and retrograde transport of the resulting proteins is thought to set up a length-dependent oscillatory signal that regulates neuronal growth rates. Indeed, perturbation of the mechanism by sequestering importin β1 mRNA or nucleolin away from axons significantly enhances neuronal growth.
Computational modeling of this intrinsic mechanism postulates the existence of a negative feedback loop for periodic resetting of the signal. Because the mechanism is critically dependent on RNA localization to axons, we considered how this might be regulated. RNA localization motifs are often located within 3′ UTRs, and 3′ UTR length can be regulated by alternative polyadenylation. We therefore examined the possibility that shortening of 3′ UTRs by alternative polyadenylation might regulate injury-induced growth of peripheral sensory neurons. This led to the unexpected identification of a subfamily of B2-SINE non-coding repeat-element (RE) RNAs as key regulators of a physiological growth circuit.
B2-SINEs are non-coding RNAs transcribed by RNA polymerase III (Pol III) from short interspersed nuclear elements (SINEs), which are high copy number transposable elements in the mouse genome. B2-SINEs are often polyadenylated, and although mostly transcriptionally repressed in somatic cells, they can be upregulated upon cellular stress. Our recent studies establish a subset of polyadenylated B2-SINE repeat elements, hereby termed GI-SINEs (growth-inducing B2-SINEs), as intrinsic axon growth regulators. This unique subset of B2-SINE RNAs integrates mRNA localization and translation to enhance sensory neuron growth after axon injury. Exogenous expression of B2-SINEs also enhances growth in central nervous system neurons that do not upregulate endogenous SINE elements upon nerve injury. The GI-SINEs are induced in response to retrograde injury signals via activation of AP-1 transcription factors and modulate growth and protein synthesis.
Valine Restriction Extends Life Span in Male Mice Only
https://www.fightaging.org/archives/2025/09/valine-restriction-extends-life-span-in-male-mice-only/
Dietary protein refers to the intake of the nine essential amino acids that cannot be synthesized by our biochemistry: valine, isoleucine, leucine, methionine, phenylalanine, tryptophan, threonine, histidine, and lysine. The single value for "protein" that regulators such as the FDA required to be provided on food packaging is derived via a complicated process that starts with one of a number of different assays used to determine essential amino acid content of a foodstuff, all of which can produce subtly different results in different foodstuffs. Those results are massaged into a single number via reference to (a) what is thought to be the optimal balance of different essential amino acids versus the actual balance in the foodstuff, (b) what is thought to be the bioavailability of the amino acids present in the foodstuff, and © a few other scaling factors with empirical evidence for their use. A sizable literature of ongoing experimentation and debate underlies this present approach.
Restriction of dietary protein is an approach used to trigger the beneficial metabolic changes that take place in reaction to a lack of nutrients. It can be combined with overall calorie restriction, or the diet structured such that calorie level remains constant even as protein intake is reduced. Many nutrient sensing mechanisms evolved to react to levels of specific essential amino acids, and consequently researchers have experimented with restriction of essential amino acids one by one rather than all at once. Most such animal studies have focused on the effects of restricting dietary methionine, and have demonstrated that methionine restriction reproduces a fair-sized fraction of the benefits of overall calorie restriction. In today's open access paper, researchers instead restrict valine, and find that while it appears beneficial in both sexes, it only extends life in male mice.
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice.
Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling.
Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
Reprogramming Research Points to GSTA4 as an Important Component of Many Age-Slowing Interventions
https://www.fightaging.org/archives/2025/09/reprogramming-research-points-to-gsta4-as-an-important-component-of-many-age-slowing-interventions/
Reprogramming involves exposing cells to the Yamanaka factors, a set of transcription factors that are involved in the conversion of adult cells into embryonic stem cells in the earliest stages of embryogenesis. In addition to converting an adult somatic cell into a pluripotent stem cell, Yamaka factor expression also rejuvenates epigenetic control over nuclear DNA structure and gene expression and restores youthful mitochondrial function. This latter process of rejuvenation has become an area of strong research interest, and a few well funded biotech companies are attempting to build therapies to treat aging and age-related conditions based on partially reprogramming the cells of a living individual.
More than one of these programs is focused on the eye, for a number of reasons. Firstly, diseases of the aging eye represent a large market. Secondly, the eye is relatively isolated from the rest of the body, making it an easier target for novel classes of therapy, such as gene therapies, that carry unknown risks. Thirdly, treating the eye requires only small doses of a drug, making it a good target for classes of treatment where manufacture remains relatively expensive. Today's open access paper arises from one program focused on reversal of retinal aging, but the discovery reported is of broader interest, with potential applications beyond reprogramming therapies. Within the field of reprogramming, this appears to be another incremental step towards to capacity to separate change of cell state from rejuvenation of cell function - a desirable goal for the research community.
Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision
Age-related macular degeneration (AMD), the leading cause of irreversible vision loss affecting over 200 million people worldwide, is a prime example of oxidative stress-driven pathology. The dry form of AMD, which accounts for 90% of cases, is driven by degeneration of the retinal pigment epithelium (RPE), a layer highly vulnerable to oxidative damage from chronic light exposure and bisretinoid lipofuscin buildup which elevates reactive oxygen species (ROS) over time. The causal role of ROS in AMD is supported by the AREDS2 study, where antioxidant supplementation slowed disease progression. The two recently approved therapies for dry AMD treatment provide only modest benefit, likely reflecting the fact that they target components of the alternative complement pathway, a cascade that is activated after oxidative stress has already injured the retina, rather than addressing that upstream damage directly. This highlights an unmet need to identify novel pathways that enhance oxidative resilience and counteract ROS-induced damage.
Over the past decade, partial epigenetic reprogramming through transient expression of all or subsets of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc, aka OSKM) has emerged as a promising strategy to restore youthful tissue function in vivo. Dual AAV-mediated delivery of OSK without the c-Myc oncogene has been shown to rejuvenate post-mitotic retinal ganglion cells (RGCs), promoting axon regeneration and restoring vision in either glaucomatous or aged mice, with long-term expression via AAV2 proving safe for up to 18 months. Notably, it has also shown promise in a non-human primate model of non-arteritic anterior ischemic optic neuropathy, a common optic neuropathy.
Despite its therapeutic potential, the mechanisms through which OSK(M) exerts functional rejuvenation remain poorly defined. A few mediators of partial epigenetic reprogramming, including Tet1/Tet2 and Top2a, have been identified, that facilitate chromatin and DNA modifications in cooperation with OSK. However, the broader network of OSK downstream effectors, those functional units that directly carry out the biological effects, remain less well explored. Here we explore the effect of OSK partial reprogramming in RPE cells, which operate under high oxidative load offering a robust model for probing how rejuvenation programs confer resistance to oxidative challenges.
Enabled by a functional genomics approach, our study uncovers a rejuvenation axis involving GSTA4 activation, that bypasses reprogramming-induced dedifferentiation. GSTA4 is a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.
The Amish as a Point of Comparison for Long-Term Effects of Physical Exercise
https://www.fightaging.org/archives/2025/09/the-amish-as-a-point-of-comparison-for-long-term-effects-of-physical-exercise/
The epidemiological paper noted here shows that Amish life expectancy compares favorably with that of the surrounding population of the United States. While lifestyle choices for the Amish differ in many ways from the general population, their greater level of physical activity is an obvious point of focus. The dose-response curve for physical activity is fairly well characterized, and suggests that ever greater benefits to health and life expectancy continue to accrue up to twice or more the presently recommended 150 minutes per week of moderate to vigorous physical activity. The health of populations like the Amish and remaining hunter-gatherers may be examples of this effect in action.
This study examines differences in the longevity of Amish men compared to the men within the general population of the United States. Data for this analysis comes from the 1965 Ohio Amish directory, specifically the birth and death dates of men from the Holmes County settlement. Amish men's longevity is compared with the white men of Ohio based on life tables published online by the Social Security Administration.
Amish men born between 1895 and 1934 who lived past their twenty-fifth birthday had an averagelifespan of 76.3 years, compared with the white men of Ohio of the same age category, who hadan average lifespan of 71.3 years, for a difference of five years. When the findings are considered with published research on Amish work practices, we concluded that the remarkable longevity of Amish men might be attributed to their exceptional level of physical activity.
The Role of Bacterial Infection in Atherosclerotic Plaque Rupture
https://www.fightaging.org/archives/2025/09/the-role-of-bacterial-infection-in-atherosclerotic-plaque-rupture/
In later life atherosclerotic plaques grow in blood vessel walls to narrow and weaken those vessels. When a plaque becomes unstable and ruptures, a downstream blockage can cause a heart attack or stroke. This and the slower harmful consequences of reduced blood flow via narrowed vessels makes atherosclerosis the largest cause of human mortality. Here, researchers provide evidence for long-lasting bacterial infection to be involved in the timing of plaque instability and rupture, particularly oral bacteria that have at some point entered the bloodstream. That said, at the point at which plaque is large enough to do this, some form of catastrophe is inevitable. The bacteria are just accelerating the process.
Using a range of advanced methodologies, the research found that, in coronary artery disease, atherosclerotic plaques containing cholesterol may harbour a gelatinous, asymptomatic biofilm formed by bacteria over years or even decades. Dormant bacteria within the biofilm remain shielded from both the patient's immune system and antibiotics because they cannot penetrate the biofilm matrix. A viral infection or another external trigger may activate the biofilm, leading to the proliferation of bacteria and an inflammatory response. The inflammation can cause a rupture in the fibrous cap of the plaque, resulting in thrombus formation and ultimately myocardial infarction.
"Bacterial involvement in coronary artery disease has long been suspected, but direct and convincing evidence has been lacking. Our study demonstrated the presence of genetic material from several oral bacteria inside atherosclerotic plaques." Tissue samples were obtained from individuals who had died from sudden cardiac death, as well as from patients with atherosclerosis who were undergoing surgery to cleanse carotid and peripheral arteries. Researchers developed an antibody targeted at the discovered bacteria, which unexpectedly revealed biofilm structures in arterial tissue. Bacteria released from the biofilm were observed in cases of myocardial infarction. The body's immune system had responded to these bacteria, triggering inflammation which ruptured the cholesterol-laden plaque.
Neural Progenitor Cell Transplantation Promotes Recovery Following Stroke in Mice
https://www.fightaging.org/archives/2025/09/neural-progenitor-cell-transplantation-promotes-recovery-following-stroke-in-mice/
Researchers here report that human neural progenitor cells derived from induced pluripotent stem cells (iPSCs) can induce some degree of recovery from stroke in mice. As expected for a cell therapy of this nature, functional recovery results from signaling provided by the transplanted cells that favorably alters the behavior of native cells. Inducing regeneration in the brain is important for more than just the damage of stroke, and so is an area of research worth keeping an eye on. In the case of stroke itself, however, more attention should be directed towards prevention: developing means of regressing atherosclerotic plaque to prevent rupture and blockage of vessels in the brain and otherwise reversing structural vascular aging to prevent breakage of vessels and consequent bleeding injury in the brain.
Stroke remains a leading cause of disability due to the brain's limited ability to regenerate damaged neural circuits. Here, we show that local transplantation of iPSC-derived neural progenitor cells (NPCs) improves brain repair and long-term functional recovery in stroke-injured mice. NPCs survive for over five weeks, differentiate primarily into mature neurons, and contribute to regeneration-associated tissue responses including angiogenesis, blood-brain barrier repair, reduced inflammation, and neurogenesis. NPC-treated mice show improved gait and fine-motor recovery, as quantified by deep learning-based analysis.
Single-nucleus RNA sequencing reveals that grafts predominantly adopt GABAergic and glutamatergic phenotypes, with GABAergic cells engaging in graft-host crosstalk via neurexin, neuregulin, neural cell adhesion molecule, and SLIT signaling pathways. Our findings provide mechanistic insight into how neural xenografts interact with host stroke tissue to drive structural and functional repair. These results support the therapeutic potential of NPC transplantation for promoting long-term recovery after stroke.
Iron Metabolism in Osteoporosis
https://www.fightaging.org/archives/2025/09/iron-metabolism-in-osteoporosis/
Here find an interesting review of what is known of the role of iron metabolism in osteoporosis, the progressive loss of bone mineral density that occurs with age. Bone tissue is constantly remodeled throughout life, the bone extracellular matrix deposited by osteoblast cells and broken down by osteoclast cells. The loss of strength and increasing fragility of bone in older people arises because of a growing imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. Thus there are many possible ways one could in principle intervene in this problem, most of these approaches not even touching on the underlying causes of the condition, but rather trying to enhance osteoblast activity or inhibit osteoclast activity in some way. As researchers here note, aspects of iron metabolism are in this list of targets for intervention.
Osteoclast-mediated bone resorption is a tightly regulated process essential for maintaining skeletal integrity. Hyperactive osteoclasts are recognized as key contributors to excessive bone loss in conditions such as osteoporosis. Osteoclasts possess a unique ability to resorb bone matrix by releasing hydrolytic enzymes and secreting acid into a specialized extracellular compartment known as the ruffled border. This resorptive function is heavily reliant on two cellular organelles: lysosomes and mitochondria. Lysosomes create an acidic environment via a vacuolar proton pump (v-ATPase), which is essential for protease production. These acidic components, including protons and proteases, are delivered into the ruffled border to degrade the aged bone matrix. Meanwhile, this bone resorption process is highly energy demanding, in which mitochondria serve as the primary energy source. Additionally, mitochondria also provide energy to lysosomes to ensure that they are well functioned in producing and releasing acidic components.
A central player linking mitochondria and lysosomes in osteoclast-mediating bone resorption is iron. Lysosomes act as major iron uptake and recycling centers, regulating iron metabolism by controlling its trafficking, storage, and redistribution. Lysosomal acidification is essential for iron uptake, reducing ferric iron (Fe3+) to ferrous iron (Fe2+), which is then released into the cytoplasm and incorporated into the labile iron pool (LIP) for utilization, storage, or export. Subsequently, mitochondria are the primary sites for iron utilization, facilitating processes, such as oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC) pathway, to generate energy and reactive oxygen species. In the context of bone homeostasis, clinical observations dating back to the early 1900s have established a connection between iron overload and excessive bone loss, underscoring the pivotal role of iron in maintaining bone homeostasis.
Building on these insights, a deeper understanding of the interactions among lysosomes, mitochondria, and iron, particularly in the context of osteoclasts and osteoporosis, is urgently needed. This review focuses on the roles of the lysosome-iron-mitochondria axis in osteoclast function and its implications for osteoporosis. We first examining the evidence supporting the pivotal function of lysosomes in regulating iron homeostasis in osteoclasts, as well as their possible involvement of iron in lysosomal biogenesis and function. Next, we summarize current knowledge on iron utilization in mitochondria and its implications for osteoclast activity. Following this, we explore emerging mechanisms underlying lysosome-mitochondria crosstalk in iron metabolism. Finally, we discuss how dysregulation of the lysosome-iron-mitochondria axis contributes to osteoclast dysfunction and highlight the potential therapeutic strategies targeting this axis for osteoporosis treatment.
Failure to Regulate Diastolic Blood Pressure as a Contribution to Cognitive Decline
https://www.fightaging.org/archives/2025/09/failure-to-regulate-diastolic-blood-pressure-as-a-contribution-to-cognitive-decline/
Blood pressure is dynamically regulated in response to circumstances and circadian rhythm. One of the issues arising with age is that this regulation is impaired, such as by the various mechanisms that stiffen blood vessels that include altered behavior of smooth muscle cells and cross-linking of the extracellular matrix. Researchers here show that dysregulation of diastolic blood pressure, in which normal variability is suppressed, can be distinctly correlated to progression of age-related cognitive decline. This is likely a reflection of shared underlying mechanisms that lead to both varied forms of vascular dysfunction in the brain and systemic dysregulation of blood pressure throughout the body.
Blood pressure variability (BPV) refers to the degree to which blood pressure fluctuates within a given time frame. Previous studies have shown a clear association between BPV and cerebral small-vessel disease (CSVD). BPV is strongly associated with the risk of developing CSVD and its severity, and systolic BPV (SBPV) has been shown to be positively associated with the incidence of cerebral white matter lesions, stroke, and cognitive decline. SBPV leads to unstable cerebral perfusion, which may result in chronic underperfusion or intermittent overperfusion, both of which can impair brain microstructure and function over time. This instability exacerbates the effects of CSVD, a key pathological substrate for vascular cognitive dysfunction, leading to lacunar infarcts, microhemorrhages, and diffuse white matter lesions, all of which are associated with cognitive impairment.
However, the above studies have focused on the effect of SBPV on CSVD, whereas the significant effect of diastolic BPV (DBPV) on CSVD is rarely reported. The interplay between DBPV and cognitive functions is multifaceted at the age where diastolic pressure is starting to decline. This complexity in variability may stem from the process of vascular aging, which is influenced by unique, individual factors not necessarily aligned with chronological age. After adjusting for multiple comparisons, it was found that a larger early and late-phase DBPV is associated with declines in attention tasks and psychomotor tasks, as well as a greater volume of white matter hyperintensities on imaging. It is generally accepted that DBPV fluctuations decrease with age, influenced by vascular aging.
A total of 383 CSVD patients were included in this study. Patients with CSVD were divided into 4 groups based on the Mini-Mental State Examination (MMSE) to compare the differences between these groups. AI = (blood total cholesterol - high-density lipoprotein cholesterol [HDL-C]) ÷ HDL-C; DBPV = standard deviation of 24-hour DBP. A logistic regression model was constructed to screen out the risk factors for cognitive dysfunction in patients with CSVD, and the model was evaluated using the receiver operating characteristic curve.
Patients with different degrees of cognitive dysfunction revealed differences in 24-hour mean diastolic blood pressure (DBP), DBPV, daytime DBP, nocturnal systolic blood pressure, and nocturnal drop in systolic blood pressure and DBP between the groups. Notably, the variability in DBP is significantly lower in the mild and moderate cognitive dysfunction groups compared to the normal cognitive function group. Additionally, the arterial stiffness index negatively correlates with cognitive decline, while showing a positive correlation with the 24-hour average DBPV. In other words, individuals with lower variability of DBP exhibited higher AI and poorer cognitive functions, emphasizing the importance of diastolic pressure stability in maintaining cognitive health. Unlike previous studies that mainly focused on the impact of systolic pressure on cognitive function, our findings suggest that variability in diastolic pressure may be an overlooked risk factor for cognitive decline.
Towards Artificial Elastin for Tissue Engineering and Regenerative Medicine
https://www.fightaging.org/archives/2025/09/towards-artificial-elastin-for-tissue-engineering-and-regenerative-medicine/
Elastin is a vital component of flexible tissues, and poorly maintained in the adult body. Deterioration of elastin is an important component of the age-related structural alterations that take place in tissues such as skin and blood vessels. Elastin is also hard to obtain or manufacture for use in engineered tissues, which is the primary roadblock motivating the research noted here. While this is useful, a robust source of elastin (or as here, elastin-like proteins that suitably mimic the behavior of elastin) would probably do relatively little to enable therapies to restore elastin structures in aged tissues, as those elastin structures are complex and the configuration of elastin molecules relative to other components of the extracellular matrix matters. It is likely that some form of reprogramming of cell behavior will be necessary to rebuild the elastin structures that were primarily laid down during development.
Our bodies contain a special protein called elastin, which has a remarkable ability to stretch like a rubber band and snap back to its original shape. This elasticity is crucial for the function of various organs, allowing the lungs to inhale and exhale, blood vessels to expand and contract with each heartbeat, and the skin to remain smooth and supple. Despite its utility, using natural elastin for medical applications is challenging. It's available in limited quantities naturally, the purification process is complex, and there's a risk of an immune reaction when administered to humans in other individuals. To address these issues, scientists developed elastin-like polypeptides (ELPs), which could be produced in large quantities but could not fully replicate the complex, precise functions of natural elastin.
Researchers have now created a new protein by selecting and reassembling the most critical parts of tropoelastin, the precursor to human elastin. They precisely combined three distinct domains - a hydrophobic domain that influences the protein's physical properties, a cross-linking domain that provides stability, and a cell-interaction domain that promotes interactions between cells. This new protein was named elastin domain-derived protein (EDDP). EDDP offers several advantages. It can be mass-produced like conventional ELPs while retaining the elasticity and resilience comparable to natural elastin. More remarkably, EDDP promotes cell adhesion and growth by transmitting signals that were lacking in conventional ELPs. This enhanced cell-interaction function directly aids cell survival and growth, making it highly effective in regenerating damaged tissues.
Betaine as an Exercise Mimetic
https://www.fightaging.org/archives/2025/09/betaine-as-an-exercise-mimetic/
Exercise has been shown to induce the synthesis of the metabolite betaine (trimethylglycine) in the kidneys. Separately, delivery of betaine was developed as a therapy for the rare disease homocystinuria due to its ability to blunt the harmful buildup of homocysteine in that condition. Here, researchers briefly review recent developments in the understanding of the ability of additional betaine delivered as a therapy to act as an exercise mimetic, triggering some of the beneficial metabolic responses to exercise.
Recently, researchers identified the renal metabolite betaine as a potent exercise mimetic through comprehensive multi-omics analysis of exercise responses, offering a promising solution for individuals unable to sustain long-term exercise. The researchers systematically characterized the differential responses to Acute exercise (AE) and Long-term exercise (LE). AE primarily induced acute metabolic and immune stress, marked by significant increases in non-esterified fatty acids, decreased total bile acids, and upregulation of inflammatory factors including IL-6 and EN-RAGE, alongside activation of the glucocorticoid receptor pathway and enhanced anaerobic glycolysis. In contrast, LE triggered sustained adaptations involving metabolic reorganization, immune remodeling, and gut microbiota restructuring. Metabolic reorganization is achieved through the coupling of fatty acid oxidation with tricarboxylic acid cycle activity, accompanied by optimized amino acid metabolism and activated antioxidant defenses. Immune remodeling is reflected by increased naive lymphocytes, reduced neutrophils, and attenuated lymphocyte aging via ETS1 downregulation. Gut microbiota restructuring is characterized by a decrease in opportunistic pathogens and suppressed lipopolysaccharide biosynthesis. Critically, LE also specifically activated methionine metabolism pathways, inducing significant enrichment of the renal metabolite betaine.
Integrated multi-omics analysis confirmed the kidney as the central organ for exercise-induced betaine metabolism, mediated by upregulation of renal choline dehydrogenase (CHDH). Mechanistic studies demonstrated betaine directly binds and inhibits the innate immune kinase TBK1, reducing lipopolysaccharide-induced release of pro-inflammatory cytokines TNF-α and IL-6 while inhibiting immune cell adhesion. Murine models further established betaine's capacity to alleviate cellular senescence, consistently reducing established aging markers including SA-β-Gal and p21. These data reveal the kidney-betaine-TBK1 axis as the core pathway coordinating exercise-mediated anti-inflammatory and anti-senescence effects.
To validate the therapeutic efficacy of betaine, researchers conducted comprehensive supplementation studies in aged murine models. They supplemented aged mice with 1% betaine daily for 8 weeks and found that betaine concentrations in the kidneys of aged mice increased to levels comparable to those induced by LE. Functional evaluation showed that aged mice had significantly improved motor coordination, muscle strength, and spatial memory ability, and significantly reduced depression-like behaviors. Histopathological analysis revealed attenuated markers of aging, reduced lipid deposition, and reduced fibrosis in the kidney, liver, lung, and skin, along with restoration of skeletal muscle morphology and epidermal architecture. Molecular analysis confirmed that betaine could inhibit the phosphorylation of TBK1/IRF3/p65 signaling pathway, down-regulate the proinflammatory cytokines TNF-α and IL-1β, and activate AMPK/SIRT1/PGC-1α signaling pathway. These collective findings support betaine as a viable exercise-mimetic intervention for counteracting age-related physiological and functional decline.
Reviewing the Role of mTOR in Aging
https://www.fightaging.org/archives/2025/09/reviewing-the-role-of-mtor-in-aging/
The mechanistic (or mammalian) target of rapamycin (mTOR) is a well studied portion of cellular biochemistry. The activity of mTOR and downstream consequences of that activity form one portion of a broad regulatory system that reacts to nutrient availability in order to change growth and stress responses in cells. Inhibition of mTOR is a necessary part of the beneficial response to fasting and calorie restriction, in which an increase in the activity of cell maintenance processes acts to improve health and slow the progression of aging. Animal studies robustly demonstrate extended lifespan in response to mTOR inhibition. In recent years a number of programs have focused on the development of novel drugs targeting mTOR, while the generic mTOR inhibitor rapamycin is widely employed by anti-aging clinics, and was the subject of a community-funded clinical trial.
Aging is a highly intricate biochemical process. There is strong evidence suggesting that organismal aging, age-dependent diseases, and cellular senescence are related to the mammalian target of rapamycin (mTOR) signaling pathway. The signaling pathway of mTOR has become a prominent regulatory hub, managing crucial cellular activities that significantly affect lifespan and longevity. The mTOR is involved in controlling cell growth and metabolism in response to both internal and external energy signals as well as growth factors. The interaction between mTOR and cellular homeostasis is crucial in the aging process.
This extensive review summarizes the most recent findings on mTOR inhibitors in the context of aging, highlighting their complex interactions with cellular systems, effect on longevity, and potential as therapeutic approaches for age-related diseases. Rapamycin and rapalogs (analogs of rapamycin), which have been proven to be effective mTOR inhibitors, have the ability to reduce the aging process in several model species while also enhancing metabolic health and stress responses.
These results suggest mTOR inhibitors as potential therapies to address the complex aspects of age-related diseases. However, obstacles stand in the way of clinical translation. Further research is required to improve dosing protocols, reduce potential side effects, and target mTOR inhibitors precisely at specific tissues.
Resistance Training Improves Peripheral Nerve Function in Older Adults
https://www.fightaging.org/archives/2025/09/resistance-training-improves-peripheral-nerve-function-in-older-adults/
Regular exercise is demonstrated to improve many aspects of health in a dose-dependent fashion. Aerobic exercise and resistance exercise have overlapping but subtly different effects, and are often studied distinctly. Program of resistance exercise have been demonstrated to reduce mortality in older individuals, and more generally the view of "use it or lose it" is supported by the scientific literature. Exercise produces benefits, and a sedentary life is harmful to long-term health. Here, researchers demonstrate that the benefits of exercise in older individuals include improved peripheral nerve function.
The natural progression of age can result in motor neuron degeneration, reflected by fewer functioning motor neuron axons and/or degradation of the motor axons. These outcomes result in the slower transmission of a nerve impulse supplying a target effector muscle and can have functional consequences such as slower movements or reduced mobility. Additionally, older adults exhibit varying degrees of loss in strength and muscle mass as a result of these effects and may become more susceptible to the development of sarcopenia.
Resistance training has long been prescribed to older adults as a means to long-term vitality. Individuals who remain active throughout their life have been known to have improved mobility, more independence, and greater life expectancy. Although previous studies have investigated training and nerve conduction speed in adults, few studies have focused on interventions that mitigate nerve speed loss and possible adaptations training may have.
The purpose of this study was 1) to quantify the effects of resistance training on nerve conduction velocity (NCV) and 2) to determine if age affects nerve plasticity in response to training. Forty-eight subjects (18-84 yr) completed this study (training: n = 14 younger, 14 older; control: n = 12 younger, 8 older). Median motor NCV and maximal strength were recorded before and after 4 weeks of handgrip training in both limbs. Training was conducted 3 times per week with the use of a grip training kit.
The results revealed significant increases in NCV for both the young (Cohen's d = 0.749) and older training groups (Cohen's d = 0.679), but neither in control groups (young: Cohen's d = 0.326; older: Cohen's d = -0.184). The results of this study suggest that resistance training may be a viable method to counteract age-related nerve deterioration.
Applying Mendelian Randomization to Support a Causal Relationship Between Frailty and Dementia
https://www.fightaging.org/archives/2025/09/applying-mendelian-randomization-to-support-a-causal-relationship-between-frailty-and-dementia/
Mining human epidemiological data can only produce correlations. Mendelian randomization is a way to add data on genetic variants known to affect disease status into the mix so as to add some support for causation. The result isn't a determination of causation, but in the best case is supportive of that conclusion. Physical frailty is well known to correlate with neurodegeneration, and a range of reasonable hypotheses exist to explain why this is the case. Both emerge from chronic inflammation and other underlying dysfunctions of aging, for example. Or frailty involves significant dysfunction in the cardiovascular system, which in turn negatively affects the aging brain. In the absence of ways to eliminate the chronic inflammation of aging or reverse vascular aging, it is hard to prove any of this. Which doesn't matter! Regardless, the right course is to try to build approaches to reverse the damage and dysfunction of aging.
Physical frailty is associated with a higher risk of developing dementia, but it remains unclear whether this relationship is causal. This prospective cohort study was based on UK Biobank participants without dementia at enrollment (between 2006 and 2010). Physical frailty was defined by 5 criteria (weight loss, exhaustion, physical inactivity, slow walking speed, and low grip strength). Incident dementia was tracked through linked hospital admission records and death registries, using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Cox proportional hazard regression models and bidirectional Mendelian randomization (MR) analyses were used to evaluate the causal association of physical frailty with incident dementia.
Among 489,573 participants (mean age 57.03 years, 54.4% female), 8,900 dementia cases were documented over a median follow-up of 13.58 years. Compared with nonfrail individuals, the risk of dementia was 50% higher in those with prefrailty (hazard ratio :1.50) and 182% higher in those with frailty (HR: 2.82). Participants with frailty and high genetic risk had the highest risk of dementia compared with those with low genetic risk and nonfrailty (HR: 3.87 for high polygenic risk score; HR: 8.45 for APOE-ε4 carriers). The forward MR analysis indicated a potential causal relationship between physical frailty and dementia (odds ratio [OR]:1.79) while the reverse MR suggested a null causal association (OR: 1.00). Structural equation modeling points to genetic background and neurologic and immunometabolic function as potential underlying mechanisms linking physical frailty to dementia.
View the full article at FightAging
