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- Correlations Between Maximum Species Life Span, Brain Size, and Immune Function
- To What Degree Does Viral Infection Contribute to Aging?
- UNITY Biotechnology Falls Victim to the Present Poor Funding Environment
- Stem Cell and Extracellular Vesicle Therapies as Treatments for Aging
- The Aged Blood-Brain Barrier is More Vulnerable to Disruption by Hypoxia
- Even Small Amounts of High Intensity Exercise Slow Brain Aging
- Joint Aging Starts Early, Particularly in Overweight Individuals
- The Road to Greater Human Longevity is Longer than Desired
- α-Synuclein Aggregation Alters Lipid Metabolism in What are Likely Harmful Ways
- HDAC11 Deficiency Slows Muscle Aging
- Protein Acetylation is Important in Mammalian Species Longevity
- Another Mutation Causing a Need for Little Sleep
- Nucleoside Reverse Transcriptase Inhibitors May Slow the Development of Alzheimer's Disease
- Does Air Pollution Contribute Meaningfully to Iron Accumulation in the Aging Brain?
- Fecal Microbiota Transplant from Young Rats to Old Rats Improves Memory
Correlations Between Maximum Species Life Span, Brain Size, and Immune Function
https://www.fightaging.org/archives/2025/05/correlations-between-maximum-species-life-span-brain-size-and-immune-function/
Researchers interested in the comparative biology of aging have focused much of their efforts on the search for genetic differences that correlate with species life span. This can be higher or lower expression in directly homologous genes, but also differences in the number of genes in a family relating to a specific function, and differences in gene sequences. As one might expect, well established genetic differences involve genes associated with mechanisms relevant to aging and life span, such as DNA repair, tumor suppression, regenerative capacity, and antioxidant mechanisms.
In today's open access paper, researchers describe a more comprehensive search for differences between mammalian species, and find that genetic differences are more related to immune system function and brain size relative to body size than they are to body size alone. This is interesting; as you might recall, body size and metabolic rate correlates decently well with species longevity. Bigger animals tend to live longer than smaller animals, and exhibit a slower metabolism. The outliers are extreme, however, such as naked mole rats that live nine times as long as similarly sized mice and tiny bats that live for decades. The outliers show there is no necessary dependency on body size, and that the real mechanisms are elsewhere. That one of those mechanisms is the state of the immune system will keep researchers busy for a while: it is a very complex, incompletely understood part of mammalian biology.
Maximum lifespan and brain size in mammals are associated with gene family size expansion related to immune system functions
Mammals exhibit high diversity in their maximum lifespan potential (MLSP, the age at death (longevity) of the longest-lived individual ever recorded in a species), ranging from less than a year in some shrew species to over a hundred years in humans and up to two hundred in bowhead whales. Unlike average lifespan, which reflects both intrinsic and extrinsic factors such as the risk of predation and resource availability, MLSP is assumed to reflect a species' inherent longevity limit and is widely available used in comparative studies focused on life history trade-offs and the genomic determinants of longevity.
Identifying the overarching genomic signatures associated with the evolution of MLSP can provide insights into the evolution of key life history traits and variations in longevity between individuals in a species. Comparative studies have linked MLSP variations to changes in gene expression profiles. Genes associated with MLSP in these studies were enriched in DNA repair, defence response, cell cycle, and immunological process related terms. Genes such as PMS2 (DNA repair), PNMA1 (cell fate determination), and OGDHL (reactive oxygen species regulation) show positive correlation with MLSP across mammalian tissues. BCL7B, which inhibits carcinogenesis through Wnt pathway regulation, and GATM, associated with oxidative stress protection, are prominently linked to increased lifespan. These molecular signatures collectively enhance cellular maintenance and stress resistance mechanisms that appear critical for extended longevity.
Here, we use a comparative genomics approach to identify genomic signatures associated with the evolution of MLSP across mammals. We examine whether MLSP variations correlate with gene family sizes (of protein-coding genes) in 46 fully sequenced mammalian species. We found significant gene family size expansions associated with maximum lifespan potential and relative brain size but not in gestation time, age of sexual maturity, and body mass in 46 mammalian species. Extended lifespan is associated with expanding gene families enriched in immune system functions. Our results suggest an association between gene duplication in immune-related gene families and the evolution of longer lifespans in mammals.
To What Degree Does Viral Infection Contribute to Aging?
https://www.fightaging.org/archives/2025/05/to-what-degree-does-viral-infection-contribute-to-aging/
While not yet rising to the level of definitive proof and quantification of risk, a fair-sized body of evidence suggests that persistent viral infection by herpesviruses and the like can drive the onset and progression of age-related disease. This work is largely focused on the brain and neurodegenerative conditions, but if the primary mediating mechanism is increased chronic inflammation, one could imagine that viral infection is important in the progression of aging more generally. With advancing age, the immune system reacts in increasingly maladaptive ways to rising levels of biochemical damage and altered cell behaviors. Constant, unresolved inflammatory signaling - and the reactions of cells to that signaling - is damaging to tissue structure and function.
Today's open access paper discusses the present consensus view of the role of viral infection on brain aging. As the authors point out, inflammation may be important, but a range of other mechanisms are likely involved. As is usually the case for any aspect of aging, it is one thing to list involved mechanisms, but quite another to know their relative importance. The research community is fairly good at identifying mechanisms. Understanding which of those underlying mechanisms are more versus less important to any specific outcome is vital to the effective development of therapies, but unfortunately it is very challenging in practice to discover this information by any means other than trial and error. Thus trial and error remains the order of the day in the development of therapies.
Neurotropic Viruses as Acute and Insidious Drivers of Aging
In the central nervous system, neurotropic viruses are a major stressor and, therefore, a major driver of aging. Epidemiological studies of multiple large biobanks have shown that patients with a history of neurological viral infection are thirty times more likely to develop a neurodegenerative disease. In addition to the pressures of viral proteins during active infection, acute and chronic viral infections disrupt the homeostasis of the cell. This occurs throughout life, with acute causes of neurodegeneration (e.g., hemorrhagic or ischemic stroke, traumatic brain injury) and chronic conditions (e.g., viral latency, metabolic disease) compounding, often synergistically.
Here, we define aging, outline the impact viruses have on the brain, and identify the overlapping pathways of viral pathogenesis and age-related neurodegeneration. Previously proposed "Hallmarks of Aging" range in number but can be generally described by three categories: altered proteostasis, genomic compromise, and senescence. Neurotropic viruses manipulate each of these categories, driving rapid neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD), and more progressive neurodegenerative conditions like Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD).
Through our contextualization of myriad basic science papers, we offer explanations for premature aging via viral induction of common stress response pathways. Viruses induce many stresses: dysregulated homeostasis by exogenous viral proteins and overwhelmed protein quality control mechanisms, DNA damage through direct integration and epigenetic manipulation, immune-mediated oxidative stress and immune exhaustion, and general energy theft that is amplified in an aging system. Overall, this highlights the long-term importance of vaccines and antivirals in addition to their acute benefits.
UNITY Biotechnology Falls Victim to the Present Poor Funding Environment
https://www.fightaging.org/archives/2025/05/unity-biotechnology-falls-victim-to-the-present-poor-funding-environment/
It is an ugly market for biotech companies seeking funding, and this has been the case for going on two years now. In this environment companies can only survive for so long. Smaller biotech companies have been fading into oblivion left and right in this past year as investors remained very risk averse. UNITY Biotechnology, developing senolytic therapies to clear senescent cells from aged tissues, is now one of the higher profile companies to run out of funding. While demonstrating some success in recent clinical trials, clearly the company hasn't achieved a glowing enough success to convince investors to continue to back further progress towards the clinic.
UNITY has pioneered the local rather than systemic use of senolytic drugs, and on the whole their results suggest that this is not a viable approach in most circumstances; it doesn't play to the strengths of senolytic drugs. Senescent cells cause issues via their inflammatory secretions, and while a nearby cell will in principle produce a larger effect with its secretions than a distant cell will, the body is large in comparison to any single organ, and there are many times more distant senescent cells than local senescent cells.
Senolytics company announces full 36-week data from ASPIRE trial and considers partnerships, mergers, or even winding down
Longevity focused biotech company UNITY Biotechnology has released complete 36-week data from its Phase 2b ASPIRE clinical study, along with a corporate update reflecting a significant shift in its direction. The company revealed it is restructuring its operations to conserve capital and pursue strategic alternatives for its pipeline programs, with a focus on reducing operational expenses and seeking external partners or transactions to advance its programs. As part of the shift, it appears UNITY will lay off its entire workforce, retaining some consulting agreements to manage the closeout of the ASPIRE study and provide continuity during the transition. Key executives, including its CEO, CFO and Chief Legal Officer, will transition to advisory roles to support the strategic review process.
Today's complete results from the trial reveal that the company's lead senolytic therapy, UBX1325, achieved vision improvements comparable to the current standard of care (aflibercept) in patients with advanced diabetic macular edema (DME) who had experienced suboptimal benefit from prior anti-VEGF therapies. At week 36, UBX1325 was statistically non-inferior to aflibercept in improving Best-Corrected Visual Acuity (BCVA), which it also achieved across most time points in the study. However, as previously reported, the trial did not meet its primary endpoint - non-inferiority in BCVA at the average of weeks 20 and 24. "Even at week 24, we met non-inferiority, so it's a very, very narrow technical definition. Having run a lot of trials, when a study doesn't work, it's rarely just one small measure falling short while everything else looks good. But that's exactly what happened in our case."
Stem Cell and Extracellular Vesicle Therapies as Treatments for Aging
https://www.fightaging.org/archives/2025/05/stem-cell-and-extracellular-vesicle-therapies-as-treatments-for-aging/
Stem cell therapies have expanded in use over the last 30 years, and are now widespread. Substituting extracellular vesicles for the stem cells is a more recent innovation, but also now widely used in the medical tourism industry. These treatments have shown effects on aging and longevity in animal studies, but we have no idea whether this is the case in humans, and we are in no danger of finding out any time soon. Even short clinical trials are expensive, while trials large enough and long enough to assess effects on life span are prohibitively expensive. There is as yet no generally accepted and trusted measure of biological age one might apply to patients before and after a treatment. The existing aging clocks will produce their results, but those results have yet to be calibrated against real-world outcomes for life span.
One is only left with the reasonable hypothesis that reducing chronic inflammation and encouraging tissue maintenance via this class of therapy will slow the progression of aging to some degree. How much of a degree? No-one knows. One pessimistic view of the field of rejuvenation biotechnology as a whole is that the recent history of stem cell medicine is a preview of the next 30 years of efforts to treat aging, in that (a) useful therapies will slowly spread into widespread clinical use, but (b) we will have no concrete measure as to how effective these therapies are when it comes to slowing or reversing aging.
With all of this in mind, today's open access paper provides a discussion of stem cell therapies and extracellular vesicle therapies from the point of view of the treatment of aging, rather than the treatment of specific conditions per se. As the authors point out, there is ample data to characterize the safety of these treatments and the beneficial suppression of inflammation produced by these treatments, but next to nothing can be said about how the observed effects on life span in animal models translate to humans.
Mesenchymal stem cells and their derivatives as potential longevity-promoting tools
Mesenchymal stem cells (MSCs) represent a distinct population of mesenchymal stromal cells, which (i) are able to adhere to plastic surfaces, (ii) express specific cell surface markers (CD73, CD90, and CD105, but not CD14, CD34, CD45, and HLA-DR), (iii) and are able to differentiate into osteogenic, chondrogenic, or adipogenic cell lineages in vitro. It should be noted that MSC isolation yields heterogeneous, non-clonal cultures of stromal cells, including stem cells with diverse multipotent potential, committed progenitors, and differentiated cells. MSCs are found in virtually all organs of the adult organism, examined thus far. A rapidly growing body of evidence indicates the beneficial effects of systemic administration of MSCs or MSC-derived extracellular vesicles (EVs) in various pathological conditions, including age-related diseases (ARDs). For example, the systemic administration of bone marrow-derived MSCs or MSC-derived EVs from young rodents increased hippocampal neurogenesis and improved cognitive function in aged animals.
Systemic administration of MSCs and stem cell/blood-derived EVs modified the omics profiles of various organs of aged rodents towards the young ones. The application of EVs appears to be even more beneficial than MSCs. Remarkably, over 70% of microRNAs, which are over-presented in ESC-derived EVs, were found to target longevity-associated genes. Along with MSCs, other types of stem cells were reported to display healthspan- and lifespan-extending effects. Pluripotent Muse cells, a specific subpopulation of MSCs, which possess a number of unique features, could be particularly relevant for promoting healthspan. The rejuvenation potential of MSCs, EVs, and Muse cells warrants further investigation in both animal models and clinical trials, using aging clocks for biological age determination as one of the endpoints.
Longevity is the most general and integrative parameter for evaluating the therapeutic effects of any interventions. Another integrative parameter directly related to life expectancy is biological age. Recently, its determination has become possible, using various biological aging clocks. However, to date, a comprehensive analysis of the impact of MSCs/MSC-derived EVs on longevity, biological age, and aging phenotypes has not been conducted. With this in mind, in this review, we primarily focus on the effects of MSC or EV administration on the lifespan of wild-type or progeroid animals. Along with the health- and lifespan-extending effects, we discuss their putative mechanisms as well as the impact on biological age and aging omics signatures.
The Aged Blood-Brain Barrier is More Vulnerable to Disruption by Hypoxia
https://www.fightaging.org/archives/2025/05/the-aged-blood-brain-barrier-is-more-vulnerable-to-disruption-by-hypoxia/
The blood-brain barrier consists of specialized cells that line blood vessels passing through the brain. These cells collectively permit only certain molecules to pass to and from the brain, maintaining the distinct biochemistry and cell populations of the central nervous system versus the rest of the body. Where the blood-brain barrier leaks, the result is inflammation and dysfunction in brain tissue as, a reaction to the presence of unexpected and unwanted molecules and cells. Unfortunately the blood-brain barrier declines and malfunctions with age, as is the case for all complex biological systems. This is likely an important contribution to the development of neurodegenerative conditions.
In today's open access paper, researchers discuss the role of hypoxia in producing blood-brain barrier dysfunction. While a local lack of oxygen will induce leakage of the blood-brain barrier at any age, older individuals are both more vulnerable and more likely to suffer conditions and states of aging that provoke hypoxia on a regular basis. Greater blood-brain barrier leakage in transiently hypoxic individuals may be an important mechanism in the link between a number of hypoxia-inducing conditions and increased risk of neurodegenerative conditions.
Defining the hypoxic thresholds that trigger blood-brain barrier disruption: the effect of age
We recently demonstrated that exposure to chronic mild hypoxia (CMH; 8% O2) in young (2 months old) mice triggers a cerebrovascular remodeling response that includes endothelial proliferation and low levels of transient blood-brain barrier (BBB) disruption that is accompanied by microglial activation and aggregation around leaky blood vessels. Strikingly, the extent of hypoxia-induced BBB disruption is greatly amplified (5-10-fold) in aged (20 months old) mice. As hypoxia is a common component of many age-related diseases including chronic obstructive pulmonary disease (COPD), asthma, ischemic heart disease, heart failure, and sleep apnea, it follows that in the elderly population, hypoxic events could trigger BBB breakdown, culminating in neuronal dysfunction, neurodegeneration, and vascular dementia. Consistent with this idea, several studies have demonstrated increased dementia risk in people who suffer from hypoxia-inducing conditions such as sleep apnea and COPD.
What hypoxic level is sufficient to trigger vascular remodeling and BBB breakdown, and how does age influence the hypoxic threshold that triggers BBB disruption? At what age do cerebral blood vessels become more susceptible to hypoxia-induced disruption? In this study, we addressed these fundamental questions by first exposing young (2 months old) and aged (20 months old) mice to a range of oxygen levels from normoxia (21% O2) to marked hypoxia (8% O2) to define the hypoxic thresholds that triggers vascular remodeling and BBB disruption at the two different ages. Next, we investigated at what specific age mice become more susceptible to hypoxia, by comparing mice of 8 different ages (from 2 months to 23 months) to a fixed (8% O2) level of hypoxia.
Analysis of brain sections demonstrated that the thresholds required to trigger hypoxia-induced BBB disruption (CD31/fibrinogen) and endothelial proliferation (CD31/Ki67) were much lower in aged mice (15% O2) compared to young (13% O2). Hypoxia-induced endothelial proliferation was relatively constant across the age range, but advanced age strongly enhanced the degree of BBB disruption (4-6-fold greater in 23 months vs. 2 months old). While the BBB became more vulnerable to hypoxic disruption at 12-15 months, a large step-up also occurred at the surprisingly young age 2-6 months. Our data demonstrates that the aged BBB is far more sensitive to hypoxia-induced BBB disruption than the young and define the hypoxic thresholds that trigger hypoxia-induced BBB disruption in young and aged mice. This information has translational implications for people exposed to hypoxia and for those living with hypoxia-associated conditions such as asthma, emphysema, ischemic heart disease, and apnea.
Even Small Amounts of High Intensity Exercise Slow Brain Aging
https://www.fightaging.org/archives/2025/05/even-small-amounts-of-high-intensity-exercise-slow-brain-aging/
The value of lower levels of physical activity has been one of the major themes of the past twenty years of research into the effects of exercise on long-term health. The advent of low-cost wearable accelerometer devices has enabled researchers to rigorously quantify differences for lesser amounts of physical activity, in order to get a much better look at the lower end of the dose-response curve for exercise. That leads to studies such as the one noted here, in which researchers assess the impact of small amounts of high intensity exercise on brain aging.
Endurance training and good fitness can reduce the risk of dementia and promote healthy brain aging. Even small amounts of physical activity may be enough to protect the aging brain, researchers recently concluded. A new paper evaluated evidence from both animal and human studies, and shows how physical activity affects inflammation, blood flow, immune function, brain plasticity and the release of protective molecules in the blood - processes that weaken with age and contribute to the development of neurodegenerative diseases.
Today, the recommendation is at least 150 minutes of moderate or 75 minutes of high intensity per week. The researchers point out that exercising much less than what the current recommendations recommend can provide great benefits - as long as the intensity of the training is high. "We believe it's time for health authorities to provide clearer advice on how important exercise is for the brain. Our review shows that even small doses of high-intensity activity - equivalent to brisk walking where you can't sing - can reduce the risk of dementia by up to 40 per cent."
Joint Aging Starts Early, Particularly in Overweight Individuals
https://www.fightaging.org/archives/2025/05/joint-aging-starts-early-particularly-in-overweight-individuals/
Measurable early signs of aging are interesting because they can serve as an easier platform for the development of therapies: there are more patients, and the patients are more physically robust. Here, researchers show that wear and tear damage to cartilage can be seen as early as the 30s, particularly in people who are overweight. Cartilage damage remains a challenge for the medical community, though a range of efforts are underway to develop and assess regenerative therapies to address this issue. That younger people might be candidates for those therapies can only increase the incentives for developers.
Mild structural changes visible in knee MRI scans are already common among adults in their thirties - even in those without knee pain or other symptoms. A study found signs of joint damage in more than half of the 33-year-old participants. A high body mass index emerged as the most common factor associated with these changes. The participants were part of the Northern Finland Birth Cohort 1986, with 297 individuals undergoing knee imaging. Each participant received a comprehensive health examination, provided blood samples, and underwent a magnetic resonance imaging scan of the knee. Their average age was 33.7 years.
The most common findings were minor articular cartilage defects, particularly between the kneecap and thighbone, observed in over half of those imaged. Cartilage defects were also found in the joint between the shinbone and thighbone in about a quarter of participants. In addition, small bone spurs, or osteophytes, were detected in more than half of the group, although these were generally small. Researchers identified a higher body mass index as the clearest factor linked to the MRI findings. Although most participants were asymptomatic, the findings suggest that structural changes in joints can occur before clear symptoms develop. The researchers stress the need for longitudinal studies to determine which factors predict the progression of these changes later in life.
The Road to Greater Human Longevity is Longer than Desired
https://www.fightaging.org/archives/2025/05/the-road-to-greater-human-longevity-is-longer-than-desired/
As noted in this article, progress towards ways to significantly extend the healthy human life span continues to be slower than desired. Further, most of the approaches to the problem are little better than exercise. One can't conjure extra decades and a reversal of aging using calorie restriction mimetic drugs. That part of the field focused on therapies that can only modestly slow aging must atrophy in favor of more viable classes of therapy, those capable of much greater repair of aged tissue, addressing the known causes of aging in order to allow youthful metabolism and tissue maintenance to reemerge.
The rise of longevity biotechnology is a modern crusade to unlock the secrets of extended life. Billions in funding have poured into startups, research labs, and bold promises of reversing aging. We have made progress: we know that human life, and especially the lives of lab animals, can be stretched impressively. Yet despite all our high-tech tools, no cutting-edge intervention, whether cellular reprogramming with Yamanaka factors or advanced drug cocktails, has outperformed rapamycin or caloric restriction in animal models, whether tested alone or in combination.
The longevity field projects a contradictory message. On one hand, it claims we are close to developing a drug against aging; on the other, it acknowledges that we still lack a shared understanding of what aging actually is. We are like early aviators tinkering with wings and engines, achieving powered flight through trial and error. Drugs that mimic the effects of caloric restriction, like rapamycin and metformin, are our first creaky airplanes: promising, but still crude.
The ambition to truly defeat aging is not just about building better airplanes; it's about realizing that no airplane, no matter how refined, can reach the moon. To get there, humanity needed rockets, which are based on entirely different principles. Similarly, halting aging will demand not just incremental improvements, but a deep, principled mastery of the fundamental mechanics that drive the aging process.
α-Synuclein Aggregation Alters Lipid Metabolism in What are Likely Harmful Ways
https://www.fightaging.org/archives/2025/05/%ce%b1-synuclein-aggregation-alters-lipid-metabolism-in-what-are-likely-harmful-ways/
The protein α-synuclein becomes prion-like when it misfolds, capable of encouraging other α-synuclein molecules to misfold the same way and assemble into solid deposits that are disruptive to cell biochemistry. This is the pathology that drives Parkinson's disease and other synucleinopathies, as α-synuclein spreads throughout the brain. Cellular biochemistry is complex and incompletely understood, and mapping the ways in which various forms of protein aggregate in fact cause harm remains an active area of research. Researchers here provide evidence for α-synuclein aggregation to alter lipid metabolism in the brain in ways that are likely harmful.
The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson's disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine.
In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species.
Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy.
HDAC11 Deficiency Slows Muscle Aging
https://www.fightaging.org/archives/2025/05/hdac11-deficiency-slows-muscle-aging/
Researchers have found that genetic engineering to reduce expression of HDAC11 favorably changes the metabolism of muscle tissue in mice regardless of age. In older mice this alteration slows the well known loss of muscle mass and strength and improves muscle regeneration. Interestingly, HDAC11 inhibitor small molecules have been identified by the cancer research community, so the next step is to assess the ability of these drugs to improve muscle function in old mice.
Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function, and globally improves muscle performance in young mice.
Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed.
HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.
Protein Acetylation is Important in Mammalian Species Longevity
https://www.fightaging.org/archives/2025/05/protein-acetylation-is-important-in-mammalian-species-longevity/
Proteins can undergo a large range of post-translational modifications, usually the addition of one or more molecules. This changes the interactions of the protein and its role in cellular biochemistry, and thus post-translational modification is an important aspect of the way in which protein machinery functions in the cell. Acetylation is one such modification, the addition of an acetyl group. Here, researchers assess the acetylome, amounts of all aceltyated proteins in tissues, in search of correlations with species longevity.
Despite extensive studies at the genomic, transcriptomic, and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals.
Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair, and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.
Another Mutation Causing a Need for Little Sleep
https://www.fightaging.org/archives/2025/05/another-mutation-causing-a-need-for-little-sleep/
It seems likely that the next century will see the engineering of new humans to have genetic alterations that have been identified as wholly beneficial. It is a lot easier to edit the genomes in an embryo than it is to adjust all of the cells in an adult in the same way, due to the issues of delivery of suitable genetic medicine to all cells in all tissues. One interesting class of beneficial gene variants are those associated with what is known as natural short sleep, a phenomenon in which a rare few human lineages need very little sleep, as little as a few hours a night. More time spent awake in a lifetime is somewhat analogous to living for longer. So far ADRB1 variants and DEC2 variants have been identified. Here, researchers show that SIK3 is another gene in which variants can produce the need for very little sleep.
Sleep is an essential component of our daily life. A mutation in human salt induced kinase 3 (hSIK3), which is critical for regulating sleep duration and depth in rodents, is associated with natural short sleep (NSS), a condition characterized by reduced daily sleep duration in human subjects. This NSS hSIK3-N783Y mutation results in diminished kinase activity in vitro.
In a mouse model, the presence of the NSS hSIK3-N783Y mutation leads to a decrease in sleep time and an increase in electroencephalogram delta power. At the phosphoproteomic level, the SIK3-N783Y mutation induces substantial changes predominantly at synaptic sites. Bioinformatic analysis has identified several sleep-related kinase alterations triggered by the SIK3-N783Y mutation, including changes in protein kinase A and mitogen-activated protein kinase. These findings underscore the conserved function of SIK3 as a critical gene in human sleep regulation and provide insights into the kinase regulatory network governing sleep.
Nucleoside Reverse Transcriptase Inhibitors May Slow the Development of Alzheimer's Disease
https://www.fightaging.org/archives/2025/05/nucleoside-reverse-transcriptase-inhibitors-may-slow-the-development-of-alzheimers-disease/
Nucleoside reverse transcriptase inhibitors (NTRIs) were developed to treat HIV infection, interfering in the ability of the virus to replicate. Researchers here present epidemiological evidence for this class of drug to slow the onset of Alzheimer's disease. The researchers focus on reduced inflammation as a driving mechanism, but it seems plausible that this outcome occurs because NTRI's interfere in harmful transposable element activities. Transposable elements such as retrotransposons are largely the genetic remnants of ancient viral infections. They make up a sizable fraction of the genome. These sequences are suppressed in youth, but with age and the epigenetic changes characteristic of aging, transposable elements become active, duplicate themselves in the genome to cause mutational damage, create particles that sufficiently resemble viruses to trigger innate immune responses, and cause other harms.
NRTIs, or nucleoside reverse transcriptase inhibitors, are used to prevent the HIV virus from replicating inside the body. Researchers previously determined that the drugs can also prevent the activation of inflammasomes, important agents of our immune system. These proteins have been implicated in the development of Alzheimer's disease, so researchers wanted to see if patients taking the inflammasome-blocking drugs were less likely to develop Alzheimer's.
To do that, they reviewed 24 years of patient data contained in the U.S. Veterans Health Administration Database - made up heavily of men - and 14 years of data in the MarketScan database of commercially insured patients, which offers a broader representation of the population. They looked for patients who were at least 50 years old and were taking medications for either HIV or hepatitis B, another disease treated with NRTIs. They excluded patients with a previous Alzheimer's diagnosis.
In total, the researchers identified more than 270,000 patients who met the study criteria and then analyzed how many went on to develop Alzheimer's. Even after adjusting for factors that might cloud the results, such as whether patients had pre-existing medical conditions, the researchers determined that the reduction in Alzheimer's risk among patients on NRTIs was "significant and substantial." The researchers note that patients taking other types of HIV medications did not show the same reduction in Alzheimer's risk as those on NRTIs. Based on that, they say that NRTIs warrant clinical testing to determine their ability to ward off Alzheimer's.
Does Air Pollution Contribute Meaningfully to Iron Accumulation in the Aging Brain?
https://www.fightaging.org/archives/2025/05/does-air-pollution-contribute-meaningfully-to-iron-accumulation-in-the-aging-brain/
The consensus on air pollution is that it increases late life mortality, largely via an increase in chronic inflammation in exposed tissues in the lung. Researchers here propose that uptake of iron from inhaled particulate matter can contribute to the age-related increase of iron that takes place in the brain, and thus cause pathology. The researchers demonstrate that this introduction of iron from airborne pollutants into the brain can occur in mice, but the question (as usual) is whether in humans this has an effect size large enough to be important versus the inflammatory consequences of air pollution.
Both excess brain iron (Fe) and air pollution (AP) exposures are associated with increased risk for multiple neurodegenerative disorders. Fe is a redox-active metal that is abundant in AP and even further elevated in U.S. subway systems. Exposures to AP and associated contaminants, such as Fe, are lifelong and could therefore contribute to elevated brain Fe observed in neurodegenerative diseases, particularly via nasal olfactory uptake of ultrafine particle AP. These studies tested the hypotheses that exogenously generated Fe oxide nanoparticles could reach the brain following inhalational exposures and produce neurotoxic effects consistent with neurodegenerative diseases and disorders in adult C57/Bl6J mice exposed by inhalation to Fe nanoparticles at a concentration similar to those found in underground subway systems (~150 µg/m3) for 20 days.
Inhaled Fe oxide nanoparticles appeared to lead to olfactory bulb uptake. Alzheimer's disease (AD) like characteristics were seen in Fe-exposed females including increased olfactory bulb diffusivity, impaired memory, and increased accumulation of total and phosphorylated tau, with total hippocampal tau levels significantly correlated with increased errors in the radial arm maze. Fe-exposed males showed increased volume of the substantia nigra pars compacta, a region critical to the motor impairments seen in Parkinson's disease (PD), in conjunction with reduced volume of the trigeminal nerve and optic tract and chiasm.
Fecal Microbiota Transplant from Young Rats to Old Rats Improves Memory
https://www.fightaging.org/archives/2025/05/fecal-microbiota-transplant-from-young-rats-to-old-rats-improves-memory/
The composition of the gut microbiome has been shown to change with age, undergoing a loss of beneficial microbes in favor of inflammatory microbes that contribute to the chronic inflammation of aging and onset and progression of age-related conditions. Researchers have comprehensively demonstrated in animal models that introducing a young microbiome into an old animal via fecal microbiota transplantation produces a lasting rejuvenation of the gut microbiome and corresponding improvements in measures of health. Here, researchers show that these benefits include an improvement in memory function in old animals.
While transplanting the fecal microbiota from young to aged rodents has been extensively studied (that is, young FMT [yFMT]), its mechanism of alleviating working memory decline has not been fully elucidated. In this report, we aimed to investigate the effect of yFMT on the working memory of aged recipient rats performing delayed match-to-position (DMTP) tasks and the associated cellular and molecular mechanisms.
The results revealed that yFMT mitigated the decline in DMTP task performance of aged recipients. This improvement was associated with a reshaped gut microbiota and increased levels of brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 1, and synaptophysin, enhancing synaptic formation and transmission. The remodeling of the gut microbiome influenced peripheral circulation and the hippocampus and medial prefrontal cortex by regulating the Th17/Treg ratio and microglial polarization. Ultimately, interleukin-4 and interleukin-17 emerged as potential key molecules driving the beneficial effects of FMT.
These observations provide new insights into the gut-brain axis, emphasizing the connection between the gut and brain through the circulation system, and suggest an immunological mechanism that may help reverse age-related declines in the gut microbiota.
View the full article at FightAging
