Fight Aging! Newsletter, April 14th 2025 – Fight Aging!

Research can be interesting even if the future development of therapies based on that research seems challenging. Today’s open access paper is chiefly interesting for its outline of the developmental and ongoing relationship between skin and the brain, and the signaling that passes between the two. It is intriguing that this relationship means that one can harvest extracellular vesicles generated by cells in the brain and use them to change skin cell behavior in order to produce scar free regeneration from injury.

However, to make this into a therapy would require either (a) a much greater understanding of the specific signaling mechanisms involved, in order to replace the vesicles with some other way to manipulate those mechanisms, or (b) the ability to maintain human organoid brain tissues at scale for the purpose of harvesting vesicles. Since the researchers harvested the vesicles directly from brain tissue, it is unclear as to which cells produced them, and which of the various types of vesicle are important to the end result. Other options seem more impractical, such as access to a lot of waste cerebrospinal fluid from young individuals. So it seems best to look on this as a tool that might lead to a better understanding of targets to suppress scarring in skin tissue, and a line of research that will take some time to come to a practical basis for therapy.

Youthful Brain-Derived Extracellular Vesicle-Loaded GelMA Hydrogel Promotes Scarless Wound Healing in Aged Skin by Modulating Senescence and Mitochondrial Function

The intricate relationship of the “brain-skin axis” has been described in the literature, with both considered to originate from the same germ layer. The neuroendocrine networks have long been well recognized, especially with the discovery of corticotropin-releasing factor (CRF), which defines the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis. The skin has been identified as a neuroendocrine organ, expressing a variety of brain and pituitary hormones, as well as multiple neuropeptides, to regulate local homeostasis in response to stress. In contrast, abnormal mental states such as stress can promote skin aging.

It remains unclear whether cultivating a healthy, youthful brain can promote the healing of skin wounds in older adults. While the tight regulatory crosstalk between brain and skin has been represented in cellular phenotypic alterations, the underlying mechanisms remain to be elucidated. Extracellular vesicles (EVs) are membrane-bound vesicles expelled from cells, body fluids, and tissue into the extracellular space and can carry materials (proteins, RNA, and DNA) from one cell to another. EVs from elderly subjects are mediators of the progressive deterioration of age-related tissue dysfunction over time. In recent decades, EV therapies have shown promise in the field of aging.

In this study, we hypothesized that brain-EVs, as a novel paradigm, regulate aging fibrocyte metabolism and functions by delivering mitochondrion-related proteins. We identified youthful brain-derived extracellular vesicles (YBEVs) and created a composite hydrogel material incorporating YBEVs that encourages scarless wound healing in aged skin. We found that YBEVs reduce the expression of senescence, senescence-associated secretory phenotypes, and inflammation-associated proteins, and even restore dysfunction in senescent cells. Furthermore, by encouraging collagen deposition, angiogenesis, epidermal and dermal regeneration, and folliculogenesis, we demonstrated that YBEV-containing composite hydrogels accelerated scarless wound healing in skin wounds of aged rats. The pro-repairing speed and effect of this composite hydrogel even matched that of young rats.

Subsequent proteomic analysis revealed the presence of numerous proteins within YBEVs, some of which may play a role in the regulation of skin energy intake, particularly through oxidative phosphorylation and mitochondrial function. In conclusion, the findings suggest that maintaining a youthful brain could potentially alleviate skin aging, and the proposed YBEV-containing hydrogel emerges as a promising strategy for addressing age-related impairments in skin healing.

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IGF-1 Expression in Skin Can Drive Age-Related Hair Loss


https://www.fightaging.org/archives/2025/04/igf-1-expression-in-skin-can-drive-age-related-hair-loss/

Aging is an accumulation of damage and dysfunction, but a quite specific collection of forms of damage and dysfunction. One can create conditions that look like premature aging, or very selective forms of premature aging of specific tissues and organs, with any number of damaging interventions, such as administration of toxins or altered expression of genes. These are not aging. Just because an intervention produces dysfunction and damage that looks like aging doesn’t necessarily mean that it has any relevance to normal aging. The details matter. It is worth remembering this point.

In today’s open access paper, the authors report on their discovery that artificially increased expression of IGF-1 in skin produces accelerated aging of hair follicles by encouraging cellular senescence. Clearing out the senescent cells or interfering in downstream targets of IGF-1 reverses this effect, restoring hair follicle function. None of this implies that IGF-1 signaling is in any way a useful target in the normal aging of hair follicles, even given that reducing IGF-1 signaling is a well studied topic when it comes to slowing aging in short-lived species, and even given evidence for increased IGF-1 signaling in skin with age. Any approach to induce greater cellular senescence in a specific cell population is going to harm its function, and there are many, many ways to go about this, few of which are relevant to cellular senescence in normal aging. To close the loop for this paper, the researchers would need to show that the treatments that work in their model of increased IGF-1 signaling also work in old mice, but they did not do that.

Targeting IGF1-Induced Cellular Senescence to Rejuvenate Hair Follicle Aging

The insulin-like growth factor-1 (IGF-1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF-1 signaling modulates organ aging remain poorly understood. In this study, we assessed age-related changes in IGF-1 expression across multiple organs in mice and identified a more prominent increase in skin IGF-1 levels with aging – a phenomenon also observed in human skin.

To explore the consequences of elevated IGF-1, we developed transgenic mice ectopically expressing human IGF-1 in the epidermis, driven by the bovine keratin 5 promoter (IGF-1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single-cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence-associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion.

Our findings indicate that excessive IGF-1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF-1 signaling via downstream mechanisms – specifically blocking acetylated p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF-1 through dietary restriction – significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

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Structural Features of DNA Differ Between Short-Lived Rats and Long-Lived Blind Mole Rats


https://www.fightaging.org/archives/2025/04/structural-features-of-dna-differ-between-short-lived-rats-and-long-lived-blind-mole-rats/

Which gene sequences are actively read by transcription machinery in the cell nucleus to produce RNA (some of which is then translated into proteins) is determined by the structure of nuclear DNA. The various assemblies of proteins making up that transcription machinery will read whatever sequence they can attach to. Regions of nuclear DNA can be packaged away and tightly furled, made inaccessible, or otherwise become accessible for a time through alterations to histone proteins, methylation of specific sites on the genome, and other strategies. All of this changes constantly in response to circumstances, many dynamic feedback loops of RNA and protein production and structural change to DNA all interacting with one another.

In today’s open access paper, researchers offer a view of DNA structure that is less commonly discussed in the context of aging and longevity. This view emerges from the use of spectroscopy, which can be employed to gain insight into different structural variants of DNA. The double helix structure familiar to laypeople is known as B-DNA, but A-DNA and Z-DNA also exist. Spectroscopy can further can be used to visualize a range of small-scale features in the chemical structure of DNA, such as sugar puckers. Evidently, however one looks at DNA and gene expression, one is going to see differences between short-lived rodents and long-lived rodents.

What can be done with this information? At present very little. As is the case for epigenetic measures, there is no bridge of cause and consequence yet built to link specific structural DNA changes and specific forms of damage and dysfunction in aging. So one can measure structural differences across life spans within species and between species of different life spans, but it doesn’t yet much help in the matter of how to build effective rejuvenation therapies.

Structural features of DNA and their potential contribution to blind mole rat (Nannospalax xanthodon) longevity

The structural architecture of DNA, extending beyond its sequence-dependent genetic code, has emerged as a critical determinant of genomic stability, cellular function, and organismal longevity. B-DNA, which has a right-handed double helix structure with Watson-Crick base pairing, can form non-B DNA structures such as hairpins, triplexes, cruciform, left-handed Z-forms, G-quadruplexes, and A-motifs under specific conditions. While canonical B-form DNA represents the classical double-helical structure, dynamic conformational shifts, such as transitions to A-DNS or Z-DNA alter biochemical properties like flexibility, stability, and protein interactions, with profound implications for aging and disease.

Structural changes, such as the transition from B-DNA to A-DNA, influence DNA stability and flexibility and are affected by factors like DNA methylation and sugar puckering. This study is the first to investigate the relationship between DNA conformational changes and lifespan in two rodent species. The analysis focused on long-lived Anatolian blind mole-rat (Nannospalax xanthodon) and shorter-lived rat (Rattus rattus), utilizing infrared spectroscopy and principal component analysis (PCA) to examine liver DNA.

Results indicated that transitions from B-form to A-form and Z-form were more prevalent in N. xanthodon than in R. rattus. However, the dominant DNA conformations in both species are in B-form. Additionally, N-type sugar puckers (C3-endo conformation), associated with these DNA forms, were more prominent in N. xanthodon. In contrast, S-type sugar puckers (C2-endo conformation), characteristic of B-DNA, were found at lower levels in N. xanthodon. Furthermore, variations in methylation-specific structural modifications of nucleobases were quantitatively assessed among these species.

The study proposes a significant connection between the long lifespan of N. xanthodon, which live underground, and their unique DNA structure, offering insights into how different DNA forms, as well as the conformations of their backbone and sugar-base components, may affect longevity, highlighting potential research avenues regarding the biomolecular aspects of aging.

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An Update on the Progress of SIRT6 Upregulation Towards the Clinic


https://www.fightaging.org/archives/2025/04/an-update-on-the-progress-of-sirt6-upregulation-towards-the-clinic/

SIRT6 overexpression slows aging in mice for reasons that are yet to be fully understood. It influences a range of different mechanisms associated with aging, including efficiency of DNA repair. Efforts to determine which of these effects are the important ones, and the relationships of cause and effect between the outcomes it produces, will likely continue for years following the first clinical use of therapies based on SIRT6 upregulation. Research is slow and biology is complicated. Here is an update on one approach to therapeutic SIRT6 upregulation, using gene therapy to introduce a variant SIRT6 gene found in long-lived individuals. Using the standard sequence would probably also work, as that is what was done in the animal studies conducted to date – but would be harder to patent and otherwise defend in the ways needed to obtain funding from biotech investors.

Longevity biotech Genflow Biosciences has commenced a gene therapy trial aimed at addressing age-related decline in dogs. The trial is designed to evaluate the safety and efficacy of the company’s SIRT6 gene therapy in extending healthspan in older canines. By targeting the SIRT6 gene, which has been linked to extended lifespan in centenarians, Genflow hopes to generate insights that could inform future treatments for both veterinary and human applications.

The study involves 28 dogs aged ten years and older. Over the course of a year, dogs receiving the therapy via intravenous injections will be compared to an untreated control group. Researchers will assess biological age using the GrimAge methylation clock, monitor changes in muscle mass and strength, evaluate mitochondrial function, track coat condition, and measure overall well-being. The six-month treatment period will be followed by a six-month observation phase to assess lasting effects. The results of the trial are expected by the end of 2025.

Genflow’s broader focus is on developing gene therapies targeting aging-related diseases in humans, with its lead compound, GF-1002, in the pre-IND phase for metabolic dysfunction-associated steatohepatitis (MASH), a prevalent chronic liver condition. GF-1002, which delivers a variant of the SIRT6 gene found to be enriched in centenarians, has demonstrated adipogenic, anti-fibrotic, and anti-tumoral properties in preclinical studies.

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Another Example of a Distinct, Inflammatory Gut Microbiome in an Alzheimer’s Patient Population


https://www.fightaging.org/archives/2025/04/another-example-of-a-distinct-inflammatory-gut-microbiome-in-an-alzheimers-patient-population/

A number of studies in recent years have shown that patients with Alzheimer’s disease have a distinct gut microbiome composition in comparison to age-match peers. The gut microbiome changes with age, losing beneficial microbes and their production of metabolites necessary for tissue function, while gaining inflammatory microbes that contribute to the characteristic increase in chronic inflammatory signaling observed in older people. When it comes to the pro-inflammatory gut microbiome of Alzheimer’s patients, it is still an open question as to whether this relationship exists because of the inflammation, in that inflammation drives the onset and progression of Alzheimer’s disease, or whether other factors are at play. For example, a more pronounced age-related immune dysfunction could be a major contributing cause of both neurodegenerative conditions and shifts in the composition of the gut microbiome.

Alzheimer’s disease (AD) is the most common form of dementia, characterized by an irreversible decline in cognitive function. The pathogenesis of several neurodegenerative disorders has been linked to changes in the gut microbiota, transmitted through the gut-brain axis. We set out to establish by case-control study methodology whether there were any differences in the composition and/or function of the gut microbiota between older resident adults in care homes with or without an AD diagnosis via analysis of the microbial composition from fecal samples. We performed primary analysis comparing controls (n = 19) against AD patients (n = 24).

These results indicate clear differences in the relative abundance of certain bacterial species and bacterial metabolites between care home residents with and without Alzheimer’s disease that could be indicative of variable gut-brain axis activity. The AD cohort had significantly higher proportions of pro-inflammatory bacterial species and fewer ‘beneficial bacteria’. We also found clear correlations between concentrations of beneficial bacterial metabolites and abundance of ‘healthy bacteria’.

AD patients had increased levels of Escherichia/Shigella and Clostridium_sensu_stricto_1, which are linked to higher levels of gut inflammation. Escherichia/Shigella species can lead to higher levels of circulating lipopolysaccharide (LPS) and have been found in greater concentrations in the gut microbiota of individuals with mild cognitive impairment and in several prior AD studies. Certain strains of Escherichia/Shigella are known to form amyloid protein structures, known as curli, similar to those seen aggregating in the brains of AD patients. Although this is not definitively linked, it does raise one possibility as to how high levels of Escherichia/Shigella could potentially contribute to increased Alzheimer’s pathology.

Similar to other studies, the AD cohort had decreased relative abundance of Bacteroides, Faecalibacterium, Blautia, and Roseburia species which are typically linked with good health. Both Roseburia and Faecalibacterium sp. are key butyrate producers and a significant decrease in the number of butyrate-producing bacteria, and subsequently butyrate, has previously been associated with AD. What cannot be determined from our data is whether the difference in microbiota is contributing to AD pathology or whether AD itself causes the microbial dysbiosis.

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Atrial Fibrillation Correlates with Increased Risk of Later Dementia


https://www.fightaging.org/archives/2025/04/atrial-fibrillation-correlates-with-increased-risk-of-later-dementia/

Researchers here explore the age-related nature of the correlation between atrial fibrillation and dementia risk. The earlier that atrial fibrillation is diagnosed in life, the higher the increased risk of later dementia. The interesting question is which of the possible mechanisms are most important in driving this relationship. The nature of atrial fibrillation suggests that both it and dementia arise from the same underlying causes, and that the atrial fibrillation is an earlier sign of those causes. It is associated with excess weight and hypertension, for example, both of which are harmful to the brain over the long term.

In a new study, the researchers assessed the independent association between atrial fibrillation (AF) and incident dementia in Catalonia, Spain. The population-based observational study included individuals who, in 2007, were at least 45 years old and had no prior diagnosis of dementia. The study included 2,520,839 individuals with an average follow-up of 13 years. At baseline, 79,820 patients (3.25%) had a recorded diagnosis of AF. In multivariable analyses adjusting for potential confounders, AF was, overall, a statistically significant but weak predictor of dementia, linked with a 4% increased risk of dementia.

However, age was found to significantly affect the association between AF and dementia. In prespecified analyses stratified by age, the strength of the association progressively weakened with increasing age: in patients aged 45-50, those with AF were 3.3 times more likely to develop dementia than those without AF. But in patients aged over 70 years, no association was found. Further analysis shows the association lost statistical significance from 70 years. By contrast, in patients diagnosed with AF before the age of 70, the condition independently increased the risk of dementia by 21%, and an even stronger effect was observed for early-onset dementia diagnosed prior to age 65, with AF increasing the risk by 36%.

Sensitivity analyses that removed cases of previous stroke during follow-up yielded similar results: AF was associated with a modest increase (6%) in the risk of dementia in the overall population, a stronger association (23% increased risk) in those diagnosed with AF in midlife (younger than 70 years old) and had the greatest effect towards early-onset dementia (52% increased risk). Therefore, patients with AF without a prior stroke still have a higher risk of dementia, with the greatest risk observed in early-onset dementia.

“The observation that the association between AF and dementia remains unchanged after excluding patients with prior stroke indicates that other mechanisms must be involved in the increased risk of dementia among AF patients. These mechanisms may include silent strokes – meaning those that showed no clinical symptoms and can only diagnosed with CT scan or MRI – and also microinfarcts, and microbleeds. Haemodynamic changes, which involve alterations in the flow and pressure of blood in the body caused by AF, and autonomic dysregulation, which refers to an imbalance in how the body controls automatic functions like heart rate, breathing, or blood pressure, could also play a role in the disease of small blood vessels in the brain associated with dementia. Additionally, systemic inflammation associated with atrial fibrillation may amplify these effects, creating a synergistic pathway that further increases dementia risk.”

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More on the MTBR-tau243 Blood Test for Alzheimer’s Disease


https://www.fightaging.org/archives/2025/04/more-on-the-mtbr-tau243-blood-test-for-alzheimers-disease/

Alzheimer’s disease progresses from an early aggregation of amyloid-β in brain tissue and mild cognitive symptoms to a later and much more harmful combination of inflammation and tau aggregation in brain tissue. A few years ago, researchers reported that measuring a tau species known as MTBR-tau243 in blood could be used to assess the state of this progression of Alzheimer’s disease, and did so as accurately as more expensive brain imaging approaches. Here find an update on this approach to testing and its continued validation in patients at various stages of the progression of Alzheimer’s disease.

Several blood tests for Alzheimer’s disease are already clinically available. Such tests help doctors diagnose the disease in people with cognitive symptoms, but do not indicate the clinical stage of the disease symptoms – that is, the degree of impairment in thinking or memory due to Alzheimer’s dementia. Current Alzheimer’s therapies are most effective in early stages of the disease, so having a relatively easy and reliable way to gauge how far the disease has progressed could help doctors determine which patients are likely to benefit from drug treatment and to what extent.

In a new study, the researchers found that levels of a protein called MTBR-tau243 in the blood accurately reflect the amount of toxic accumulation of tau aggregates in the brain and correlate with the severity of Alzheimer’s disease. Analyzing blood levels of MTBR-tau243 from a group of people with cognitive decline, the researchers were able to distinguish between people with early- or later-stage Alzheimer’s disease and separate both groups of Alzheimer’s patients from people whose symptoms were caused by something other than Alzheimer’s disease.

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Doxifluridine Manipulates Gut Microbe Activities to Extend Life in Nematodes


https://www.fightaging.org/archives/2025/04/doxyfluridine-manipulates-gut-microbe-actitivies-to-extend-life-in-nematodes/

RNA splicing is the process by which RNA is assembled from intron and exon sequences in genes. A given gene can be assembled into different RNAs depending on what is included or excluded. The balance of different RNAs produced from a gene tends to change with age, and this may be a cause of dysfunction. Starting from a position of screening for compounds that reduce age-related dysregulation in RNA splicing in nematode worms, researchers happen upon a compound that achieves this goal and extends life by manipulating the activities of gut microbes. Determining how and why life extension occurs in this case will take somewhat longer than the discovery of the approach – it need not have anything to do with RNA splicing. It seems unlikely that this specific compound will be relevant to mice or humans, given the large differences in the gut microbiome between lower animals and mammals, but someone will get around to checking in mice at some point.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drugs can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative used in chemotherapy, rescues age-associated AS defects and extends lifespan.

Combining bacterial DNA sequencing, proteomics, metabolomics, and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate the drug’s functions through complex interplay among drug, bacteria, and host.

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Reviewing What is Known of the Effects of Partial Reprogramming


https://www.fightaging.org/archives/2025/04/reviewing-what-is-known-of-the-effects-of-partial-reprogramming/

Full reprogramming of cells occurs in the early embryo, driven by Yamanaka factor expression, the factors used often abbreviated to OSKM. It turns adult germ cells into embryonic stem cells, resetting epigenetic patterns and restoring mitochondrial function. Researchers have replicated this process to produce induced pluripotent stem cells from any adult cell sample. Partial reprogramming is intended to expose cells to Yamanaka factor expression for long enough to produce the reset of epigenetic patterns and improvement in mitochondrial function, but not for so long as to change cell state in other ways. This is thought to be a promising path to the production of rejuvenation therapies, but there are many challenges to overcome on the way to the clinic. Not least of these is that different cell types in any given tissue may have quite different requirements in terms of length of exposure or level of exposure to produce beneficial reprogramming with mimimal risk of generating potentially cancerous pluripotent cells.

Partial and full reprogramming can partially reverse age-related transcriptomic and epigenetic changes. Yet, it is unclear to what extent aging clocks are measuring biological age or cellular/organismal health. Regardless of what epigenetic aging clocks measure exactly, there are other biomarkers of rejuvenation that can be measured in partial reprogramming experiments. For example, if cycles of short-time reprogramming factor expression are followed by a recovery phase, phenotypic rejuvenation effects can be observed. By default, rejuvenation markers must be evaluated on a tissue-by-tissue basis.

An intriguing example is the brain, where cyclic OSKM without a recovery phase restores the proportion of neuroblasts and improves the production of neurons in vivo. Moreover, in vivo studies performed on mouse neurons and rat dentate gyrus cells suggest that OSKM can reverse age-associated neurological decline and enhance memory. Other mouse in vivo studies have shown that reprogramming enhances liver regeneration, promotes the repair of crushed optic nerves and ameliorates aging-associated loss of visual acuity, allows for muscle fiber regeneration, improves skin wound healing in aged mice, and promotes heart rejuvenation following myocardial infarction.

The mechanism of rejuvenation appears to partially depend on how cells are reprogrammed. Indeed, it was found that the mechanism of somatic cell reprogramming via small molecule regimens is distinct from transcription factor-mediated reprogramming. By constructing chromatin landscapes, researchers identified hierarchal histone modifications and sequential enhancer recommissioning which underlies regeneration programs following chemical reprogramming; this regeneration program appears to reverse the loss of regenerative potential in organismal aging but apparently it is not activated in OSKM reprogramming.

Reprogramming specific cells in vivo affects surrounding tissue. For example, it was found that in vivo activation of OSKM in myofibers led to proliferation of satellite cells in the stem cell niche of the myofibers, without inducing myofiber dedifferentiation; likely these changes are at least partially modulated via changes to the extracellular matrix (ECM). In fact, the ECM and its constituents are frequently affected by partial reprogramming. As mice age, collagen-associated transcript levels decrease in the pancreas but increase again, at least partially, following OSKM treatment with a two-week recovery period. Also, in fibroblast and adipocyte mesenchymal cell experiments with no recovery period, some ECM-associated processes are upregulated by partial reprogramming, including pathways linked to collagen.

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Shingles Vaccination Correlates with Lower Dementia Risk


https://www.fightaging.org/archives/2025/04/shingles-vaccination-correlates-with-lower-dementia-risk/

Why would people who underwent shingles vaccination in later life exhibit a lower risk of later developing dementia? Firstly, one has to elect to take this vaccine, and so this could be selecting for people who tend to take better care of their health, and thus are in better shape than their peers, on average. Secondly, vaccination produces an effect called trained immunity that makes people incrementally more resistant to the chronic inflammation of aging. Lastly, there is some evidence for persistent viruses such as the varicella-zoster virus that causes shingles to contribute to the onset and progression of dementia, for reasons yet to be fully understood. Epidemiological studies such as this one don’t shed much light on biological mechanisms, but do add expected value to seeking vaccination rather than passing it up.

Shingles, a viral infection that produces a painful rash, is caused by the same virus that causes chicken pox – varicella-zoster. After people contract chicken pox, usually in childhood, the virus stays dormant in the nerve cells for life. In people who are older or have weakened immune systems, the dormant virus can reactivate and cause shingles. Previous studies based on health records have linked the shingles vaccine with lower dementia rates, but they could not account for a major source of bias: People who are vaccinated also tend to be more health conscious in myriad, difficult-to-measure ways. Behaviors such as diet and exercise, for instance, are known to influence dementia rates, but are not included in health records.

But two years ago, researchers recognized a fortuitous “natural experiment” in the rollout of the shingles vaccine in Wales that seemed to sidestep the bias. The vaccination program specified that anyone who was 79 was eligible for the vaccine for one year. People who were 80 were out of luck – they would never become eligible for the vaccine. The researchers looked at the health records of more than 280,000 older adults who did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold – comparing people who turned 80 in the week before with those who turned 80 in the week after. The same proportion of both groups likely would have wanted to get the vaccine, but only half, those almost 80, were allowed to by the eligibility rules.

Over the next seven years, the researchers compared the health outcomes of people closest in age who were eligible and ineligible to receive the vaccine. By factoring in actual vaccination rates – about half of the population who were eligible received the vaccine, compared with almost none of the people who were ineligible – they could derive the effects of receiving the vaccine. As expected, the vaccine reduced the occurrence over that seven-year period of shingles by about 37% for people who received the vaccine, similar to what had been found in clinical trials of the vaccine. Seven years later, one in eight older adults, who were by then 86 and 87, had been diagnosed with dementia. But those who received the shingles vaccine were 20% less likely to develop dementia than the unvaccinated.

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Chronic Inflammation is Central to Aging


https://www.fightaging.org/archives/2025/04/chronic-inflammation-is-central-to-aging/

While short-term inflammation is useful and necessary, such as in the response to infection or injury, that same inflammatory signaling sustained over the long term becomes harmful. It becomes disruptive to tissue structure and function, altering the behavior of cells in damaging ways. Chronic inflammation is a feature of aging, and clearly contributes to the onset and progression of all of the common age-related conditions. It seems unlikely that age-related chronic inflammation can be effectively prevented, other than by removing the various forms of underlying cell and tissue damage that provoke continual maladaptive inflammatory responses. While one can suppress specific inflammatory signals in blunt ways, that only affects some inflammation, and also suppresses the normal, short-term inflammation necessary for defense against pathogens and regeneration from injury.

The relationship between aging and peripheral inflammation represents a complex and multifactorial process, with many molecular mechanisms contributing to a prolonged state of chronic low-grade inflammation, also called inflammaging. In contrast to acute inflammation, which is a transient response to infection or injury, inflammaging is a persistent, low-grade inflammatory state that develops as a result of the combined influence of internal and external factors accumulated throughout life. This process is characterized by sustained immune pathway activation, the increased production of pro-inflammatory cytokines, and the dysregulation of immune homeostasis, all of which contribute to the progressive functional decline associated with aging.

Aging affects multiple peripheral organs, including the liver, adipose tissue, skeletal muscles, and gastrointestinal tract, all of which play a crucial role in modulating systemic inflammation. The progressive dysfunction of these organs with age is primarily caused by molecular and cellular alterations, including oxidative stress, genomic instability, epigenetic changes, mitochondrial impairment, and cellular senescence. All of these create an inflammatory microenvironment that evokes tissue damage, ultimately contributing to the onset and progression of many age-related diseases, including cardiovascular disorders, neurodegenerative conditions, and cancer. At the molecular level, inflammaging involves a complex network of inflammatory mediators, including cytokines, acute-phase proteins, and damage-associated molecular patterns (DAMPs), which activate various intracellular signaling pathways.

A defining feature of inflammaging is the senescence-associated secretory phenotype (SASP). As aging occurs, senescent cells accumulate in several tissues, promoting a pro-inflammatory environment that supports immune system activation and drives tissue remodeling. An additional factor in inflammaging is gut microbiota dysbiosis, which has become increasingly recognized as a significant regulator of systemic inflammation in aging individuals. Age-related alterations in gut microbiota composition can result in increased intestinal permeability, facilitating the translocation of bacterial endotoxins, such as lipopolysaccharide (LPS), into the circulation. This process triggers sustained immune cell activation, further enhancing systemic inflammation.

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Calorie Restriction and Calorie Restriction Mimetic Drugs Restore More Youthful Lipid Metabolism


https://www.fightaging.org/archives/2025/04/calorie-restriction-and-calorie-restriction-mimetic-drugs-restore-more-youthful-lipid-metabolism/

The practice of calorie restriction improves health and extends life, though the effect on life span is much larger in short-lived species such as mice than in long-lived species such as humans. Researchers here focus on changes in lipids in mice that result from calorie restriction and a number of different calorie restriction mimetic drugs. One of course expects fat tissue to change greatly as a result of a low calorie diet sustained over time, but changes in lipid levels and distributions of different lipids change throughout the body. Calorie restriction mimetic drugs only capture a fraction of the overall effects of calorie restriction, but still tend to push things in a similar direction. The interesting observation here is that, overall, these changes look like rejuvenation, tending to move measures lipid metabolism towards a more youthful outcome.

Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose.

These interventions generally have a stronger effect in males than in females. Using Jonckheere’s trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney.

We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.

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β-hydroxy-β-methylbutyrate Improves Health and Slightly Extends Life Span in Flies


https://www.fightaging.org/archives/2025/04/%ce%b2-hydroxy-%ce%b2-methylbutyrate-improves-health-and-slightly-extends-life-span-in-flies/

It is always interesting to see data on life span in short lived species for an intervention with a fair amount of human data for health benefits. The broad pattern is that short-lived species exhibit a much greater extension of life in response to interventions, but on the other hand near all of the data is focused on only a few different ways to alter metabolism, such as the upregulation of stress responses and increased cell maintenance observed in calorie restriction. Supplementation with β-hydroxy-β-methylbutyrate is yet another way to manipulate the systems of regulation linking nutrient availability and cell maintenance, in an attempt to capture some fraction of the benefits of exercise and calorie restriction.

Two lifestyle interventions that may improve muscle function and attenuate the negative physical outcomes of the aging process include exercise and dietary protein and amino acid supplementation. At the molecular level, leucine serves as a direct substrate for muscle protein synthesis as well as an activator of protein synthesis through the multi-protein complex mechanistic Target of Rapamycin Complex 1 (mTORC1). Branched-chain amino acid aminotransferase transaminase (BCAT) converts leucine to keto-isocaproic acid (KIC), which is then reduced to 𝛽-hydroxy-𝛽-methylbutyrate (HMB). Dietary HMB supplementation has been shown to have a positive effect on muscle function in several rodent studies and human trials.

A growing body of evidence suggests that HMB supplementation improves lean body mass composition and muscle function in older subjects, and can mitigate loss of lean mass in elderly subjects during periods of bed rest. Several mechanisms of HMB action on muscle have been described, including both an anabolic mechanism through an up-regulation of protein synthesis via the mTOR pathway, and an anti-catabolic mechanism through a down-regulation of muscle protein breakdown via the ubiquitin-proteasome proteolytic pathway.

We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, we found that HMB attenuates the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health.

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