Fight Aging!

A peptide is a short protein. There are countless such molecules present in the body. If used as a basis for therapy, a peptide is generally injected rather than taken orally as only a very small range of peptides can survive the digestive tract. Indeed, only a very small number of proteins more generally can survive outside of their specialized location inside a cell. So when people talk about peptides for therapy, they are talking about a tiny fraction of the peptides present in the body, largely those that are in some way involved in signaling between cells and thus can be found circulating through blood and tissues. Of that still very large number of peptides, a handful have been developed or are under development as potential therapies.

In recent years the same sort of people who enthusiastically sell dietary supplements on the basis of minimal data, cherry-picked studies, and a lot of hype and marketing have now discovered the existence of injectable peptides. There is something of a craze developing for a handful of known peptides that include a few approved for use with specific conditions outside the US, a few that have some animal studies and no human data whatsoever, and others in between those extremes. That GLP-1 receptor agonists are peptides has only fueled this hype cycle.

The US regulatory system for medicine has some quirks. One of those quirks is the existence of compounding pharmacies, regulated by states rather than the federal government. Very roughly, there is a whitelist of compounds that a compounding pharmacy is allowed to sell to patients, and that whitelist is largely determined by whether anyone has published a rigorous manufacturing protocol, regardless of whether or not the compound was approved for use in patients by the FDA. A lot of peptides being sold by the enthusiasts fall into this category. Further, the supplement industry is also in its own regulatory category, distinct from any sort of FDA drug approval, and also largely focused on manufacturing and quality control. Supplement industry lobbyists are apparently trying to have peptides included into their remit as well (a tough sell for injectable compounds to be called dietary supplements, but people do like to follow the money; a lot of self-interest at work there).

Needless to say, there are those on the more scientific and pro-regulation side of the house who are horrified by this sudden expansion of what they see as a blight upon the way things should be run. If they haven't been as vocal about the supplement industry in recent years, it is because they have been worn down by its excesses over the decades. Generally these commenters are in favor of the federal regulatory status quo for drugs to be more broadly applied. I think that the sane position is to be strongly against the present regulatory status quo, as it is clearly harmful to the pace of technological progress in medicine, while also recognizing that (a) it isn't great that some people are taking unnecessary and often ill-advised risks in the matter of peptides, and (b) education is an ethically better approach than regulation by force. People will sometimes do stupid things; freedom comes with responsibility. Trying to take away freedom of choice has side-effects that cause more harm over the long term, as we can see from the way in which the enormous and largely unnecessary costs imposed on medical development have impeded progress towards longer, healthier lives.

Unregulated Peptide Use in the Age of Biohacking: Digital Promotion, Gray-Market Access, and Emerging Public Health Risks

The recent expansion of peptide-based medicines has been especially visible in metabolic disease. GLP-1 receptor agonists and related incretin-based therapies have reshaped the treatment of type 2 diabetes and obesity, with agents such as semaglutide and tirzepatide demonstrating substantial effects on body weight and cardiometabolic outcomes in clinical trials. However, the visibility of approved peptide therapies has coincided with rising nonclinical peptide experimentation. The public success of GLP-1 receptor agonists has made injectable metabolic therapies more visible and normalized in public discourse, particularly for goals related to weight, metabolism, and body composition.

This legitimacy appears to be spilling over into a less regulated consumer marketplace, where experimental, investigational, or weakly evidenced peptides are promoted for fat loss, injury recovery, longevity, cognition, libido, aesthetics, sleep, muscle gain, and performance enhancement. The concern is not that all peptides are equivalent, but that digital discourse and online access pathways may blur distinctions between approved medicines, compounded products, investigational drugs, research chemicals, context-specific clinical therapies, preclinical compounds, and products supported mainly by anecdote or marketing.

This blurring is amplified by biohacking culture, longevity medicine, wellness clinics, and influencer-led health optimization. Biohacking and do-it-yourself biology communities have been shaped partly through online forums and digital spaces where users exchange knowledge, techniques, protocols, and interpretations of biological self-experimentation. In peptide-related discussions, compounds are frequently framed as tools for optimization, recovery, performance, aesthetics, cognition, or longevity, with terms such as "stacks," "protocols," "research peptides," "tier lists," and "longevity peptides" creating a shared language of self-experimentation. These digital sources should not be interpreted as evidence of clinical efficacy or safety. However, they are relevant to public health because online creators, forums, and wellness communities can influence how health products are perceived, normalized, sourced, combined, and interpreted outside formal clinical supervision.

Gray-market access is central to this exposure pathway. Many peptide products are sold online with disclaimers such as "for research use only" or "not for human consumption," while being discussed in consumer spaces as substances for personal use. Certificates of analysis, purity claims, and biomedical language may provide reassurance, even when products have not undergone the regulatory review, manufacturing oversight, or postmarketing surveillance expected for approved medicines. In this gray-market environment, access may appear medically adjacent while remaining weakly accountable, poorly traceable, and difficult to monitor through conventional pharmacovigilance systems.

Sleep quality is well established to decline with age and age-related disease. A sizable medical and supporting industry is devoted to attempts to improve sleep quality via what are essentially compensatory approaches to intervention. As researchers note here, the evidence to hand does not demonstrate that reduced sleep quality causes an acceleration in the pace of aging. That the evidence for poor sleep to cause accelerated aging is very mixed suggests a complex relationship between this dysfunction and the broader scope of aging, in which only some of the circumstances and mechanisms associated with poor sleep may accelerate aging. Otherwise it is likely a downstream consequence of aging.

Sleep gets worse with age and is correlated with risk for disease and mortality. The possibility that poor sleep causes aging to accelerate has prompted interest in improving sleep to slow aging and prevent disease. However, the existing evidence on the link between poor sleep and accelerated aging is unclear. Here, we tested for correlation and causation between poor sleep and accelerated aging using five independent datasets of adults (total N > 64,000).

We found strong evidence for a correlation between poor sleep and fast aging that is consistent across young, middle, and late adulthood and across aging biomarkers derived from different tissues and modalities. We found that this correlation is robust to the influence of chronic disease burden, but not to the influence of shared genetic and early environmental factors among twins. Finally, we found mixed evidence for a causal influence of poor sleep on accelerated aging using Mendelian randomization. Our findings indicate that the correlation between poor sleep and accelerated aging is highly robust; however, the claim that poor sleep causes aging to accelerate is not consistently supported.

Link: https://doi.org/10.64898/2026.07.02.26357135

A useful side-effect of publishing under a copyleft license is that one can be lazy about formally publishing compilations of past material. Sooner or later someone else will get around to it. Thus Kris Borer, a longevity community advocate, recently let me know that he has assembled and tidied up a collection of some of my short essays and published it as a book. The pictures of me that end up on conference websites (and now on a book cover) are looking ever younger than the reality these days; a reverse Dorian Gray effect in which fortunate lighting at the time of capture and additional post-processing every time someone copies an picture of me for a new use conspire to hide the lines. For all the promise of medical technology to hand and medical technology to come, we're all still aging faster than we'd like.

Aging is damage. Damage is repairable. Get to work. For nearly a quarter century, a writer known only as Reason said this almost every day - to a world that mostly wasn't listening. He said it when curing aging was a punchline. He said it as the science caught up, the first companies formed, and the money and the clinical trials arrived. He built, without quite meaning to, the most complete record we have of a scientific field being willed into existence - and then, in 2018, he stopped writing about other people's companies and founded his own.

The Voice of Reason gathers sixty-nine of his best pieces: the science of why we age and how we might not; a blistering quarrel with everyone who calls death a gift; the politics of which cures get made; his own self-experiments with biohacking; and, beneath it all, an unblinking reckoning with mortality - his readers', and his own. He is clear, he is blunt, he is often very funny, and he is angrier than you expect about the hundred thousand people who die of aging every day. He is also, it turns out, a man whose quarter-century forecast is coming true.

Link: https://www.amazon.com/Voice-Reason-Quarter-Century-Fighting-ebook/dp/B0H96F89Z3

Every cell contains hundreds of mitochondria, the evolved descendants of what were once symbiotic bacteria. Much of the original mitochondrial DNA has migrated into the cell nucleus, and mitochondria have become essential components of the cell, subject to quality control mechanisms that recycle malfunctioning and worn mitochondria, as is the case for other organelles. Nonetheless, mitochondria still behave very much like bacteria. They divide to make up their numbers, fuse together, and readily exchange component structures and proteins. Mitochondria are vital to cell function in a number of ways, the most important of which is their production of the chemical energy store molecule adenosine triphosphate (ATP). Cells rely upon ATP to power the chemistry of life.

With advancing age, mitochondria throughout the body change in size, structure, and function. They generate a greater amount of damaging oxidative molecules in the course of making ATP, and the production of ATP declines. Quality control is impaired and malfunctioning mitochondria accumulate. Some are made to malfunction as a result of damage to the remnant mitochondrial genomes, other dysfunction appears to be a consequence of age-related changes in the level of expression of critical mitochondrial genes found in the cell nucleus. This mitochondrial dysfunction also generates continual inflammatory signaling via maladaptive interactions between damaged mitochondria and their debris and defense mechanisms in the cell.

In today's open access paper, the authors propose a quite different view of mitochondrial dysfunction. In their hypothesis, there is a decline in the ability of mitochondria to appropriately adapt to the lower demand for ATP in aged tissues. Without appropriate regulation, excess material for the production of ATP keeps on arriving to clutter up the environment, giving rise to the observed side-effect of increased production of oxidative molecules and other issues. It is an interesting point of view, and seems worthy of an attempt to produce supporting experimental evidence.

Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability

Frailty is a clinical syndrome of reduced physiological reserve and disproportionate vulnerability to stressors in older adults. The dominant cellular model attributes frailty to mitochondrial bioenergetic insufficiency, supported by convergent evidence of reduced mitochondrial respiratory capacity, lower mitochondrial DNA (mtDNA) content and altered substrate metabolism in frail individuals across multiple tissues. Several reproducible features of the phenotype are nevertheless difficult to reconcile with a strict bioenergetic deficit interpretation. Particularly consequential for the present proposal is that cellular energetic demand itself declines progressively with age. Sedentariness, reduced muscle mass, anabolic resistance and the involution of brown adipose tissue together reduce cellular ATP turnover, shifting the balance between substrate input and demand toward chronic excess of input relative to consumption.

Building on these considerations, we propose a complementary framework in which frailty originates in energetic congestion, a state in which a chronically reduced demand allows substrate to persist beyond utilisation, while substrate input itself remains broadly preserved, with the consequence that the regulatory coupling between substrate availability and cellular need is progressively lost. Mitochondrial dysfunction in this view is real but reframed in its directionality. The mitochondrion is not failing because fuel is scarce. It is failing because the fall in demand-driven ATP turnover is not matched by a comparable reduction in substrate delivery, so that oxidative flux is uncoupled from cellular need, while mitochondrial adaptability, the capacity of the organelle to coordinate output with fluctuating energetic demand, is progressively impaired.

The thymus is primarily noted as being the site of T cell maturation, essential to the supply of new T cells to maintain the adaptive immune system. It declines in function relatively early in aging; active tissue is largely replaced by fat in most 50 year olds. Like all organs, cells in the thymus also generate various factors that circulate throughout the body. The production of these factors also declines with age as the thymus atrophies. Researchers here identify one such factor, thymulin, which appears to meaningfully affect myeloid immune cells to help control inflammatory signaling and improve immune surveillance of cancer.

Chronic inflammation increases with age and contributes to cancer progression and therapeutic resistance, yet the mechanisms underlying this process remain incompletely understood. Here, we identify an increased frequency of pro-inflammatory myeloid cells in aged mice and humans, characterized by elevated production of IL-1α, IL-1β, IL-6, and TNF-α. These cells are enriched in the breast tumor microenvironment and are associated with accelerated tumor progression.

Using heterochronic parabiosis and bone marrow chimeras, we show that age-associated myeloid cell inflammatory activation is suppressed by non-bone marrow-derived circulating factors present in young hosts. Integrative analyses identify thymulin, a thymus-derived peptide that declines with age, as a mediator that suppresses pro-inflammatory cytokine production by inhibiting NF-κB signaling. Furthermore, thymulin enhances antitumor T-cell immunity, improves tumor control and survival, and sensitizes tumors to anti-PD-L1 therapy in an age-dependent manner.

Together, these findings uncover a thymus-myeloid cell regulatory axis linking aging, inflammation, and cancer immunity, and suggest thymulin as a potential strategy to improve cancer immunotherapy in older individuals.

Link: https://doi.org/10.1038/s41467-026-75383-0

A magnetic resonance imaging (MRI) approach known as diffusion tensor image analysis along the perivascular space (DTI-ALPS) can be used to measure the flow of cerebrospinal fluid leaving the brain via the glymphatic system, a network of vessels that parallels blood vessels passing out of the brain. This drainage of cerebrospinal fluid allows metabolic waste to leave the brain, but becomes progressively ever more impaired with advancing age. It is thought that this loss of drainage leads to a build up of protein aggregates such as misfolded amyloid-β that contribute to the onset and progression of neurodegenerative conditions. Here researchers review the evidence for a reduced drainage rate measured via DTI-ALPS to correlate with established measures of the progression of Alzheimer's disease. One might recall that some animal studies have shown that forcing an increase in glymphatic flow of cerebrospinal fluid has produced a reduction in neurodegenerative pathology.

Although the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is widely utilized as a proxy for glymphatic function in Alzheimer's Disease (AD) research, its association with core AD pathological biomarkers remains inconclusive due to inter-study heterogeneity. This systematic review aimed to investigate associations between the DTI-ALPS index and AD biomarkers and to elucidate potential sources of heterogeneity.

Thirty-six studies were included. Meta-analyses revealed significant correlations between the DTI-ALPS index (N = 22) and amyloid-β positron emission tomography (PET) deposition (N = 9), Mini-Mental State Examination (MMSE) (N = 15), and Montreal Cognitive Assessment (MoCA) (N = 10) scores. Conversely, the association with tau PET deposition (N = 3) was not significant after adjusting for publication bias. Regarding clinical staging, indices were significantly lower in AD and mild cognitive impairment groups compared to controls but no difference was found between the two patient groups. Based on meta-regression and narrative synthesis results, we identified methodological variability and AD pathological complexity as primary sources of heterogeneity.

Link: https://doi.org/10.3389/fnagi.2026.1832525

As the name might suggest, aquaporin proteins facilitate the transfer of water molecules across cell membranes. This is important in a broad range of contexts, such as the operation of the blood-brain barrier that wraps blood vessels that pass through the brain, and in the drainage of cerebrospinal fluid from the brain into the body. One of the paths by which cerebrospinal fluid exits the brain, carrying away metabolic waste with it, is the glymphatic system. Glymphatic vessels run parallel to the blood vessels that enter and exit the brain. Research is making it increasingly apparent that drainage of cerebrospinal fluid is vital to the health of the brain. Unfortunately this drainage becomes progressively ever more impaired with advancing age, and this is thought to contribute to the buildup of protein aggregates and other forms of metabolic waste in the brain, contributing to inflammation, cell dysfunction, and neurodegenerative conditions.

In today's open access paper, researchers build on past work on the manipulation of aquaporin 4 (AQP4) activity in the glymphatic system. A small molecule compound TGN-073 increases the activity of AQP4 via a mechanism that isn't understood, but may involve altering the structure of AQP4 to broaden the size of the pores it creates in the cell membrane. Other work has shown that different isoforms and thus structures of AQP4 are more effective than the usual version, for example. Here, researchers show that this increased AQP4 activity does in fact help to reduce neurodegenerative pathology in mice, supporting the importance of failing cerebrospinal fluid drainage in the development and progression of neurodegenerative conditions.

AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice

The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.

The immune system and its supporting organs and structures throughout the body, such as bone marrow, spleen, lymphatic system, and thymus, are collectively make up a very complex system. The way in which the immune system ages is thus also very complex. Different specialized cell populations change in number and function. Immune cells are influenced into maladative inflammatory behavior by some combination of internal molecular damage and disarray on the one hand coupled with external damage to tissue on the other. The supply of many types of immune cell is much reduced from youthful levels, allowing malfunctioning and senescent immune cells to accumulate. The immune system is crucial to health, not just as a defense against pathogens and potentially cancerous cells, but also due to its role in day to day tissue maintenance. Improving immune function in older people is likely to produce meaningful benefits. There are certainly many, many distinct issues to provide starting points for those who wish to develop novel therapies with that goal in mind.

Aging is accompanied by complex structural and functional immune system changes driven by genomic instability, epigenetic alterations, mitochondrial dysfunction, telomere attrition, loss of proteostasis, deregulated nutrient sensing, and the accumulation of senescent cells exhibiting a senescence-associated secretory phenotype, which altogether lead to severe consequences including altered antimicrobial defense, the overproduction of autoantibodies, and chronic, low-grade inflammation (inflammaging).

In this article, we summarize age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes. The involution of these organs leads to impaired hematopoiesis, reduced production of naïve lymphocytes, and immune microenvironment disruption. We also describe aging-related impairment of the activity of neutrophils, macrophages, dendritic cells, and natural killer cells, as well as dysregulation of T lymphocyte and B lymphocyte responses. Specifically, these alterations include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors. Consequently, older individuals exhibit increased susceptibility to infections, cancer, and autoimmune diseases, along with diminished vaccine efficacy.

Link: https://doi.org/10.3390/ijms27136037

Clonal hematopoiesis of indeterminate potential (CHIP) is a form of somatic mosaicism in the immune system. Hematopoietic stem cells and progenitor cells in the bone marrow responsible for producing immune cells acquire random mutations over time, and patterns of these mutations slowly spread out into the immune system as a result. There is evidence for CHIP to correlate with accelerated progression of a number of age-related conditions and other aspects of degenerative aging, making it a good place to start if trying to understand how important somatic mosiacism is to the progression of aging. While the research community largely agrees that DNA damage is important in aging, based on the existence of accelerated aging conditions in which DNA repair mechanisms operate poorly, it is by no means concretely established as to how much of a contribution DNA damage makes to normal aging. Expect to see further investigation of CHIP and its effects on measures of aging and age-related dysfunction as an approach to answering that question.

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Five studies comprising 7,483 individuals (ages 55-79, 67.1% female) assessing associations between CHIP and DNAm clocks were included.

Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n=6,946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years), HannumAge EEAA (MD=2.31 years), PhenoAge (MD=1.84 years), and GrimAge (MD=1.20 years,). Both DNMT3A- and TET2-mutated CHIP were associated with higher EAA with TET2-mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A-mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.

Link: https://doi.org/10.1016/j.arr.2026.103259

The thymus is a tiny organ near the heart responsible for generating T cells of the adaptive immune system. Thymocyte cells are made in the bone marrow, migrate to the thymus, and undergo a process of exposure and selection that leads to mature T cells. The adaptive immune system needs a supply of new cells to make up the losses incurred due to damage and the Hayflick limit on replication. Unfortunately, the thymus atrophies with age; it is one of the earliest organs to reach a significant loss of function. Most 50-year olds have little active thymus tissue left, and a sizable component of the subsequent accelerating decline of the adaptive immune system takes place because it is denied sufficient reinforcements. It becomes ever more populated by senescent, exhausted, and malfunctioning T cells.

There are strategies that will absolutely, definitely regenerate the aged thymus, well demonstrated in animal models. None of them are all that practical for widespread use in medicine, or at least not palatable to those in charge of the regulation of medicine. Upregulation of FOXN1 via gene therapy regrows the thymus, but no delivery system other than direct injection has emerged to enable sufficient delivery to such a small organ without overloading and harming other tissues. Direct injection is not palatable because any sort of introduction of a needle into the inner organs of an aged individual has a small but meaningful rate of severe complications. This also rules out the use of KGF protein therapy, shown to regenerate the thymus in animal studies, but which cannot be introduced into humans at high enough levels via intravenous injections without causing unacceptable side-effects in other tissues.

Currently those working in the field of thymus regeneration are focused on a few different strategies. Firstly there are potential cell therapies that use cell populations known to home to the thymus, such as thymocytes and thymic epithelial cells. One can even engineer the cells, say to secrete KGF for example. Then there are a range of quieter and not yet successful efforts to find some clever way to use a small molecule or a biologic to tweak the metabolism of the thymus without upsetting any of the other tissues in the body. Existing targets, particularly those close to FOXN1, make that difficult to achieve. Lastly there is the Intervene Immune approach of tailored growth hormone therapy, which produces thymic restoration to a similar degree as observed following long term mild calorie restriction.

The good news for today is that someone is claiming to have found a viable small molecule approach to regeneration of the aged thymus that works via intraperitoneal injection in mice, a popular stand-in for intravenous injection. The treatment duration was quite short, only a few weeks. The number of mice per group is sadly low, 5 for some of the data, as low as 3 for some of the rest. That is low enough that I would want to see this replicated with 12 or more mice per group before taking it at face value. The small molecule in question is a free fatty acid receptor agonist, with the free fatty acid receptor GPR40 as the target; this agonism appears to compensate for a reduction in expression in this receptor, but how exactly this interacts with what is known of the FOXN1-centered biochemistry regulating thymic growth and activity remains to be seen. It could be as simple as reduced inflammation in thymic tissue, as reductions in inflammatory signaling are a known outcome of GPR40 agonism, but very little in biology tends towards being simple.

GW9508-Induced Activation of GPR40 in Thymic Epithelial Cells: A Therapeutic Strategy to Delay Thymic Aging

The thymus plays a crucial role in T-cell development and the establishment of cellular immunity. Thymic epithelial cells (TECs), which constitute the predominant stromal cell population in the thymus, are vital for maintaining thymic structure and function. With aging, the thymus undergoes gradual involution, characterized by a reduction in thymic volume, a decline in TEC numbers, and an accumulation of fibroblasts, adipocytes, and senescent cells within the thymic microenvironment. These changes result in decreased production of naïve T cells and reduced diversity of peripheral T-cell receptors (TCRs), ultimately compromising immune function in the elderly.

GW9508 is a selective agonist of GPR40, a receptor extensively studied in the context of metabolic diseases, and more recently, in relation to age-associated disorders. GPR40, also known as free fatty acid receptor 1 (FFAR1), is predominantly expressed in pancreatic β-cells and insulin-secreting cell lines, as well as in enteroendocrine cells, gustatory cells, immune cells, splenocytes, and the brain. Within immune system, GPR40 is implicated in regulating the functions of various immune cell, including keratinocytes, macrophages, and neutrophils. However, the role of GPR40 in senescent TECs has not been documented.

Here, GW9508, a selective agonist of GPR40, was used to treat aged C57BL/6J mice and aged iTECs model. The results indicated that targeted activation of GPR40 can activate the AMPK signaling pathway while inhibiting the ERK1/2-MAPK pathway, thereby enhancing the viability and restoring the function of aged iTECs. In vivo experiments in 17-month-old mice confirmed the effects of GW9508, consistent with cellular assays results, demonstrating that GW9508 effectively restored thymic function and facilitated structural recovery. Although thymus dysfunction begins relatively early in life, a recent study showed that it retains substantial protective capacity in adults, strongly supporting the notion that enhancing thymus function holds significant potential for improving T-cell function in older adults.

A number of neurodegenerative conditions, including Alzheimer's disease, are characterized by a pervasive chemical alteration of tau protein that causes tau to cease its normal function and aggregate into structures known as neurofibrillary tangles. This is harmful to neurons and their normal, necessary function. The feedback loop between maladaptive inflammation and tau aggregation drives the end stages of Alzheimer's disease, causing widespread cell death in the brain and the eventual death of the patient. Researchers here identify a compensatory maintenance process in neurons that can be made to operate more efficiently by increasing the expression of a protein called SORLA. In mice engineered to develop tau pathology, greater SORLA expression slows the progression of neurodegeneration.

Recent genome-wide association studies have linked multiple gene variants with altered Alzheimer's disease (AD) risk, including the class I membrane receptor endosomal trafficking factor, SORLA, or "Sortilin-related receptor containing LDLR class A repeats" (encoded by the SORL1 gene, also known as LR11). SORLA is a component of the retromer endosomal trafficking complex. Expression of retromer components have been shown to be down-regulated in AD and reduced SORLA expression was also linked to AD.

A role for SORLA in reducing amyloid-β (Aβ) levels has been well established; however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that SORLA up-regulation can attenuate pathological effects in aged PS19 tauopathy mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, long-term potentiation (LTP) impairment, and glial hyperactivation. These results indicate that SORLA confers neuroprotection against tau toxicity in the PS19 mouse brain.

Link: https://doi.org/10.1126/sciadv.aed6825

One of the hallmarks of dysfunctional lipid metabolism in the brain the context of age-related neurodegenerative disease is an increase in lipid droplets in brain cells. This is seen in a number of different neurodegenerative conditions. Evidence suggests lipid metabolism dysfunction to be involved in the inflammatory behavior of the innate immune cells known as microglia, thought to be an important contributing cause of neurodegeneration. Here, researchers provide evidence for lipid droplet formation to be associated with cellular senescence, a state in which cells cease to replicate and secrete inflammatory signals. Senescent cells are not cleared efficiently in aged tissues, and their numbers grow to disrupt tissue structure and function. It is already known that some fraction of overly inflammatory microglia in the aging brain are senescent; it remains to be seen as to the degree to which lipid metabolism dysfunction contributes to the burden of cellular senescence or vice versa.

Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking.

Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology.

Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.

Link: https://doi.org/10.18632/aging.206390

The gut microbiome changes with age in ways the provoke chronic inflammation and tissue dysfunction. Animal studies demonstrate that restoring a youthful gut microbiome to old individuals extends life and improves health. Thus we would expect favorable changes to the gut microbiome to be reflected in any good alternative measure of aging, such as aging clocks. With that in mind, in today's open access paper the authors report on the development of algorithms based on gut microbiome composition that are predictive of epigenetic clock results. This allows identification of specific microbial species that may be harmful or helpful in the matter of the pace of aging.

The eventual destination for this field of research is to produce probiotic or other forms of therapy that can permanently adjust the composition of the gut microbiome in a controlled way. Reduce the numbers of bad species, increase the numbers of good species, and do this for at least hundreds of different species. At present a number of approaches can rejuvenate the gut microbiome with a single treatment, but in an uncontrolled way. For example, fecal microbiota transplantation from a young donor. Animal studies show that fecal microbiota transplantation produces sizable benefits, but for human medicine, given the present regulatory environment, widespread use of such a gut microbiome altering therapy is only likely given complete control over both the contents of the therapy and the outcomes of the therapy.

Gut microbiome signatures associate with DNA methylation-based biological aging

Recent advances in machine learning have applied novel tools to aging research, yet the relationship between the gut microbiome and epigenetic aging remains underexplored. This proof-of-concept study investigates whether gut microbial composition is associated with biological aging pace independent of chronological age. Using paired 16S rRNA gene sequencing and DNA methylation data from 123 monocyte-enriched samples in a cohort including Native Hawaiian and Pacific Islander participants, we developed "EpiBiome" models to predict epigenetic age acceleration residuals and DunedinPACE, a DNA methylation biomarker that estimates the instantaneous pace of biological aging.

Models predicting residuals of traditional clocks (Horvath, Levine, GrimAge2) showed no predictive signal at either taxonomic rank. By contrast, the EpiBiome-Accel model for DunedinPACE reached statistical significance at both the species level (R2 = 0.152) and the genus level (R2 = 0.099,). Adding chronological age as a feature did not improve performance (ΔR2 = -0.046 at species level), indicating age-independence. SHAP analysis of the species-level ElasticNet model identified Bifidobacterium adolescentis as the dominant contributor and the strongest predictor of decelerated aging, with Succinivibrio dextrinosolvens showing the strongest association with accelerated aging. These findings reveal specific gut taxa as hypothesis-generating candidates for mechanistic follow-up, rather than as individual-level diagnostic markers.

The biochemistry of aging is enormously complex, and it is very hard to pick apart which changes are definitively cause versus effect, and which changes are definitively more important than others. The only robust approach is to build a therapy that fixes just one change in isolation, and observe the results. This is not always possible or practical. When it can be done, a great deal is learned, however. See the outcome of the development of the first senolytic drugs on the state of knowledge regarding the role and relative importance of senescent cells in degenerative aging, for example. But the lack of such targeted and relatively effective therapies for most other potentially important mechanisms of aging allows a wide diversity of viewpoints to arise, as any new hypothesis regarding the importance of any given form of damage or dysfunction is hard to prove or disprove.

Aging is often framed as the gradual erosion of proteostasis, driven by declining chaperone capacity, impaired degradation, and dysregulated protein synthesis. Yet this view implicitly assumes that proteins fail primarily because they misfold or escape clearance. Increasing evidence instead points to a more fundamental problem: aging disrupts the spatial management of the proteome. Gradually, proteins are misplaced, signaling pathways are uncoupled from their compartments, and condensates that were once dynamic become pathological.

At the center of this spatial collapse lies nucleocytoplasmic protein partitioning. Nucleocytoplasmic protein transport has long been treated as a background housekeeping process, that is, essential but largely passive. However, this assumption is no longer reasonable. Karyopherins, the importins, exportins and biportins that mediate selective transport across the nuclear pore complex (NPC), are emerging as active regulators of proteostasis, phase behavior, and signaling fidelity. Rather than simply responding to cargo demand, karyopherins shape intracellular protein solubility, suppress aberrant condensation, and buffer age-associated stress. Their dysfunction therefore constitutes a primary, not secondary, driver of aging phenotypes.

Here, I argue that karyopherins should be repositioned at the core of aging biology. I propose that age-dependent failure of karyopherin-mediated transport represents a unifying mechanism linking proteostasis collapse, altered gene regulation, and the emergence of age-associated diseases. This perspective redefines nucleocytoplasmic protein transport from a logistics challenge into a central regulatory layer and highlights karyopherins as emerging targets for aging interventions.

Link: https://doi.org/10.1111/acel.70634

Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body. Like macrophages, microglia are deeply involved in tissue maintenance as well as defense against pathogens and destruction of potentially cancerous, malfunctioning cells. Microglia adopt different packages of behaviors, called polarizations. In an aged tissue environment, microglia have a greater tendency to adopt an inflammatory polarization focused on defense rather than an anti-inflammatory polarization that aids in tissue maintenance. This shift towards maladaptive inflammatory signaling and immune behavior is characteristic of aging more generally. In the brain, microglia-driven inflammation harms tissue function, contributing to the onset and progress of neurodegenerative conditions.

Microglia, the resident innate immune cells of the central nervous system, are central players in brain development, healthy aging, and degenerative pathology, including Alzheimer's disease (AD). Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression.

In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia's molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.

Link: https://doi.org/10.3390/cells15131159