Fight Aging!

The authors of this open access paper provide an overview of two viewpoints on the onset and progression of neurodegenerative conditions. The biochemistry of the brain is exceptionally complex, and its dysfunction is also complex. It is clear that the aggregation of a few forms of altered protein is important in neurodegeneration, but exactly how and why it is important remains an active area of research. There are points of consensus, points of debate, and this landscape shifts over time as new evidence emerges. The absence of curative therapies for neurodegenerative conditions is a symptom of the inability to determine the critical mechanisms driving dysfunction, distinguishing them from the many interacting consequences of those mechanisms and other changes associated with degenerative aging.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneering researchers have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases.

The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation.

Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.

Link: https://doi.org/10.3389/fnagi.2024.1370580

One of the tasks in which machine learning and related techniques excel is finding patterns in very large data sets and extrapolating those patterns to predict as yet undiscovered members. The outcome of combinations of known small molecule drugs and drug candidates is one such data set. There is very little known in certainty about polypharmacology, as research and development groups operate under incentives that strongly discourage assessment of combination treatments. Where researchers have looked into combinations of small molecules in the context of slowing aging, they have found that the typical outcome is that any two compounds that individually alter metabolism to modestly slow aging produce no benefit or a mild harm when combined. This is a vast space of possibilities, little concrete knowledge, and maybe some useful outcomes hidden in the dross - and that is exactly the sort of challenge in which machine learning can be used accelerate the pace of discovery. That said, at the end of the day we are talking about effect sizes that are, at best, on a par with that of exercise. This isn't the path to radical life extension.

The genetic foundation of lifespan is becoming increasingly well-understood, but the optimal strategies for designing interventions to extend it remain unclear. Small molecule drugs, the mainstay of the pharmaceutical industry, act by modulating the activity of gene products - proteins, herein referred to as targets. Standard drug-discovery practice dictates that therapeutic compounds should be highly specific to a single target. However, closer inspection of FDA-approved drugs reveals that some of the most efficacious drugs bind multiple targets simultaneously and that, in some instances, more specific analogs are less efficacious. These findings suggest polypharmacology may improve efficacy for some complex indications.

The largest unbiased longevity screen of the Library of Pharmacologically Active Compounds (LOPAC), particularly FDA-approved drugs, identified a significant cluster of compounds that extend lifespan by modulating neuroendocrine and neurotransmitter systems. We observed that most inhibitors of G-protein coupled receptors (GPCRs) bind multiple structurally related targets, suggesting that polypharmacological binding increases their efficacy in extending lifespan. To test this notion, we used statistical and machine learning tools, specifically graph neural networks (GNNs), to identify geroprotector compounds that simultaneously bind multiple biogenic amine receptors and then evaluated their efficacy on the lifespan of Caenorhabditis elegans.

Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to all geroprotectors recorded in the DrugAge database. Thus, our study reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.

Link: https://doi.org/10.1111/acel.70060

SQSTM1 is also known as P62. The protein expressed by this gene assists in the selection and transport of materials to be recycled via autophagy, an important stress response mechanism. Once a protein or structure has been decorated with a ubiquitin molecule, SQSTM1 binds to that protein or structure as a part of the complicated process of shuttling it to a lysosome where it can be broken down. Thus too little SQSTM1 impairs autophagy and more SQSTM1 can enable more efficient autophagy. This can influence the pace of aging, as illustrated by the numerous interventions that both slow aging and which feature enhanced autophagy. In at least a few such cases, such as for calorie restriction, autophagy has been shown to be necessary for slowed aging to occur. Unfortunately, this class of approaches to the treatment of aging has much larger effects on life span in short-lived species than it does in long-lived species such as our own.

In today's open access paper researchers review some of the biochemistry immediately surrounding SQSTM1 and autophagy, with a particular focus on cellular senescence and skin aging. Senescent cells accumulate in aging tissue, generating inflammatory signaling that is disruptive to tissue structure and function. More efficient autophagy appears to help resist entry to the senescent state, and can thus in principle reduce the burden of senescent cells in aged tissue to some degree over time, assuming the immune system is competent enough to catch up on its task of destroying senescent cells. Clinical trials in humans to conclusive prove this point and quantify the size of the benefits remains an aspiration, even for very well established drugs like rapamycin.

SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation

USP7 regulates intracellular protein homeostasis through selective substrate degradation. It plays a crucial role in cell cycle control, senescence, and cancer by interacting with diverse target protein. Sequestosome1 (SQSTM1 or p62), hereafter p62, an autophagy receptor, has been associated with aging and age-related diseases, including neurodegeneration, infections, cancer, and oxidative stress-related conditions. p62 deficiency is associated with a shorter lifespan, elevated oxidative stress, synaptic deficiencies, and memory impairment. By interacting with GATA4, p62 promotes selective autophagic degradation, inhibiting cellular senescence.

In the dermis, fibroblasts regulate collagen expression and maintain skin integrity. However, senescent fibroblasts contribute to dermal thinning, increased wrinkle formation, and skin sagging. Keratinocytes also play a pivotal role in shaping the senescent skin microenvironment, including the maintenance of the dermal-epidermal junction and the secretion of senescence-associated secretory phenotype (SASP) factors. Notably, senescent keratinocytes exhibit enrichment of SASP components, including proinflammatory cytokines and proteases. The consequent decline in cellular and tissue regenerative potential is implicated in the progression of skin aging. However, the precise mechanisms through which p62 regulates keratinocytes in skin aging are unknown.

In this study, we investigate the function of p62 and potential mechanisms in skin aging and cellular senescence. We identified p62 as a negative regulator in skin aging and senescent keratinocytes. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of USP7 during senescence induction by orchestrating its degradation through specific binding interactions. Importantly, this study provides the first time, to our knowledge, that p62 plays a critical role and regulates specific mechanisms in skin aging and cellular senescence.

A sizable portion of the health benefits (and life extension in short-lived species) resulting from the practice of calorie restriction is triggered by sensing of levels of specific amino acids. Methionine is one of the more important such amino acids, and researchers have demonstrated that low-methionine diets can produce some fraction of the benefits of calorie restriction without reducing calorie intake, at least in rodents. Just as there are calorie restriction mimetics, molecules that trigger some of the same biochemical responses to calorie restriction, there should in principle be methionine restriction mimetics. Researchers here discuss one such methionine restriction mimetic, though note that nowadays everything in this part of the field is filtered through the lens of treating obesity, regardless of possible benefits to people of normal weight, because obesity has become the primary focus of the pharmaceutical industry.

Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet.

Male obese C57BL6/NTac mice were fed high-fat diets with (a) 0.86% methionine (CD), (b) 0.12% methionine (SAAR), (c) SAAR diet supplemented with a GSH biosynthetic precursor, (d) N-acetylcysteine in water (NAC), and (e) CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes.

BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.

Link: https://doi.org/10.18632/aging.206237

Chronic inflammation is a major component of aging, disruptive to tissue structure and function. Researchers here review some of what is known of the immune system dysfunction associated with cerebral small vessel disease, noting various measures reflective of inflammation. A number of lines of evidence point to inflammation of the vascular endothelium, the inner lining of blood vessels, as important in the development of vascular conditions such as atherosclerosis and small vessel disease. One should expect sustained inflammation to be disruptive to all of the structures and functions of vascular tissue, however, including the all-important blood-brain barrier that lines blood vessels in the brain.

Cerebral small vessel disease (cSVD) refers to all pathologies of the brain's arterioles, capillaries, and venules. cSVD is highly prevalent with ageing and is diagnosed by its characteristic neuroimaging features. Emerging evidence suggests that circulating immune cells play an important role in cSVD's pathology. However, the specific immune cell populations involved remain poorly understood. This systematic review synthesizes current evidence on circulating immune cells in cSVD and their associations with cSVD features. A systematic search was conducted and a total of 18 studies were included, all studies investigating the association between peripheral immune cells and imaging features of cSVD. Data was extracted on study design, immune cells and cSVD measures, and outcomes.

Pro-inflammatory monocytes were associated with the severity and progression of cSVD over time. The neutrophil-to-lymphocyte ratio (NLR) showed positive associations with white matter hyperintensities (WMH) and enlarged perivascular spaces. The monocyte-to-HDL ratio (MHR) demonstrated a stronger association than the NLR with WMH, lacunes, and cerebral microbleeds. The lymphocyte-to-monocyte ratio (LMR) was linked to slower WMH progression and lower cSVD prevalence. Key findings highlight a role for pro-inflammatory circulating monocytes, NLR, MHR, and LMR in cSVD patients. These derived ratios serve as more reliable disease predictors than individual blood counts, showing potential as innovative diagnostic and prognostic markers. However, the reviewed studies predominantly employed cross-sectional and retrospective designs, suggesting the need for large-scale, prospective investigations to determine the role of these inflammatory markers in cSVD's pathogenesis.

Link: https://doi.org/10.1007/s10522-025-10250-x

The testes manufacture testosterone, generally important to long-term health. Further, germ cells resident in the testes manufacture sperm. This process of spermatogenesis is necessary for reproduction. Both of these functions decline with age. As is the case for near all outcomes of degenerative aging, the research community has yet to construct a clear model of cause and effect that reaches from the known root causes of aging to declining function in the tests. Cellular biochemistry is complex and incompletely mapped, and aging is a further complexity imposed upon those systems, not just as the level of individual cells, but also at the level of tissues containing enormous numbers of interacting cells of different types. It is a challenging task.

Researchers regularly uncover intermediary mechanisms in aging that appear important. Not a root cause and not a final outcome, but something in the middle layer of complex interactions that is influential enough on the progression of disease or loss of function to be worthy of note. Today's open access paper is an example of the type, in which researchers observe that loss of the capacity for ketogenesis in Leydig cells in the testes that are responsible for the production of testosterone appears important in the functional decline of the testes. This may be a target for the development of drugs to slow some of the more important age-related deterioration that takes place in this organ, though it seems that β-hydroxybutyric acid supplementation works well enough.

Impaired ketogenesis in Leydig Cells drives testicular aging

Testicular aging is characterized by a reduction in testosterone, which is linked to various male reproductive disorders and a diminished quality of life in the elderly. Currently, testosterone replacement therapy (TRT) serves as the primary intervention for alleviating symptoms associated with testicular aging. However, TRT is accompanied by notable adverse effects. Moreover, TRT fails to mimic the physiological secretion patterns of testosterone and can negatively impact spermatogenesis. Consequently, there is a pressing need to explore novel therapeutic strategies for addressing testicular aging.

Aging testes undergo profound alterations in both germ cells and somatic cells, leading to reduced functionality. Previous studies have shown that testicular aging is marked by a decline in the number of spermatogonia and spermatocytes, as well as the accumulation of DNA damage and mutations within germline cells. As the primary cells producing testosterone, Leydig cells (LCs) play a crucial role in spermatogenesis and male fertility. LCs are thought to be vulnerable to age-related damage, primarily due to oxidative stress induced by reactive oxygen species (ROS).

In this study, we characterize testicular aging by detecting the senescence marker senescence-associated β-galactosidase (SA-β-gal), identifying that LCs are the most susceptible cells to aging in the testis. Single-cell transcriptomics reveals a significant downregulation of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), which encodes the rate-limiting enzyme in ketogenesis, in aged LCs. Moreover, silence of Hmgcs2 in young LCs impairs ketogenesis, causing premature senescence and accelerating testicular aging. Mechanistically, β-hydroxybutyric acid (BHB), a ketogenic product and inhibitor of histone deacetylase 1 (HDAC1), promotes Foxo3a expression by enhancing histone acetylation, thereby alleviating LCs senescence and improving steroidogenic function.

In vivo studies further demonstrate that enhancing ketogenesis via Hmgcs2 overexpression or BHB supplementation reduces LCs senescence and improves testicular function in aged mice.

The tumor suppressor protein p53, encoded by the gene TP53, is thought to be a component of the trade-off between tissue maintenance and cancer risk that contributes to species life span. Too much p53 activity and cancer risk declines but life span shortens as tissue maintenance is also suppressed. To little p53 activity and life span increases, but so does cancer risk - eventually to the point of cutting short that extended life. Evolution comes to some balance for any given niche, but perhaps there is something to be learned from other species that could inform possible approaches to the control of cancer in our own species.

Several molecular mechanisms have been purported to regulate aging and influence lifespan - many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes and induces tumor-suppressive processes such as DNA repair, apoptosis, and cellular senescence. In a context-dependent manner, its DNA-repair mechanism enhances longevity while aberrant apoptosis and cellular senescence accelerate aging.

Genotype-phenotype correlation studies that have sought to map observed differences in lifespan across species to differences in the sequence and structure of p53 ortholog have largely focused on the DNA-binding domain (DBD). For closely related p53 orthologs, those of longer-lived species possess unique mutations in their DBD that have been hypothesized to enhance their longevity-regulating interactome. Residues 180-192, which compose the L2 region of the DBD in human p53, are most highly correlated with longevity.

Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) domains are largely unexplored. To address this, we developed a Relative Evolutionary Scoring (RES) workflow to comprehensively investigate the changes in full-length p53 structure across organisms of various taxonomic orders and observed average lifespan. Using the Sorting Intolerant From Tolerant (SIFT) mutation prediction tool and the results from yeast-based functional assays, we characterized the effect of found RES-predicted longevity-associated residues (RPLARs) on p53 function and tumor-suppressive pathways.

Our findings reveal that while most longevity-associated residues are found in the DNA-binding domain, critical residues also exist in other p53 domains. Mutational functional experiments and protein interaction predictions suggest these residues may play a vital role in p53 stability and its interactions with other proteins involved in the induction of senescence. This work broadens our understanding of the mechanisms undergirding dysregulated p53 tumor suppression and its link to accelerated aging.

Link: https://doi.org/10.1371/journal.pcbi.1012382

It is well established that hearing loss and cognitive decline correlate with one another. There is some debate over causation, the degree to which hearing loss might contribute to cognitive decline versus both outcomes arising from the same underlying mechanisms of cell and tissue damage that drive aging. Recent studies strongly suggest that loss of hearing does accelerate cognitive decline, but this doesn't rule out shared contributions to both conditions from underlying processes or a bidirectional relationship of mutual causation.

Hearing loss (HL) of moderate or higher grades is common in older adults with increasing prevalence as people age, rising from 12% at the age of 60 years to over 58% at 90 years. HL in midlife is one of the main potentially modifiable risk factors for dementia. It is estimated that 7% of dementia cases globally could be avoided if this risk factor was eliminated.

Participants from the Brazilian Longitudinal Study of Adult Health were evaluated in three study waves (2008-10, 2012-14, and 2017-19). HL was defined as pure-tone audiometry above 25 dB in the better ear. Cognitive performance was evaluated with six tests related to memory, verbal fluency, and trail-making tests. A global cognitive z-score was derived from these tests. The association between HL and cognitive decline was evaluated with linear mixed-effects models adjusted for sociodemographic, lifestyle, and clinical factors.

Of 805 participants (mean age 51 ± 9 years), 62 had HL. During follow-up, HL was associated with faster global cognitive decline (β = -0.012). In conclusion, HL was significantly associated with a faster rate of global cognitive decline after a median follow-up of eight years in a sample of middle-income country.

Link: https://doi.org/10.1177/13872877251315043

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.

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.

Link: https://doi.org/10.1016/j.neures.2025.04.005

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.

Link: https://doi.org/10.1186/s12989-025-00622-z

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.

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.

Link: https://www.eurekalert.org/news-releases/1083000

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.

Link: https://doi.org/10.1073/pnas.2500356122

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."