Fight Aging!

Senescent cells accumulate with age and contribute to degenerative aging via their pro-growth, pro-inflammatory signaling. Even when less than 1% of all cells are senescent in a tissue, the signaling generated by those senescent cells alters the behavior of other cells for the worse, and is disruptive to tissue structure and function. When it comes to what to do about the burden of senescent cells in aged tissues, much of the focus is on the development of senolytic drugs that can selectively destroy these errant cells to some degree. The most popular alternative path is the development of senomorphic drugs that can suppress senescent cell signaling to some degree, but unlike the senolytic development community this cannot yet boast the large number of companies dedicated to producing novel drugs.

Just as there are a great many senolytic compounds in the small molecule libraries and even among presently approved small molecule drugs, there are also a great many senomorphic compounds. Quality varies widely, and, sadly, all too few outperform the effects of lifestyle choices on the burden and behavior of senescent cells. Those that do are relatively neglected by the medical and development communities because they are cheap and out of patent protection; there is not enough profit to be made to support the high costs of clinical trials. So even relative well-known senomorphics like rapamycin are far less widely used than they might be, and it is left to the very slow pace of the academic community to scrape up sufficient funds to conduct large-enough clinical trials to convince more physicians to prescribe for their patients.

Senomorphics are drugs that have to be used continuously, and are unlikely to suppress all problem signaling. Senolytics are drugs that can be used intermittently, and are unlikely to kill all senescent cells. There are clearly trade-offs of cost and convenience in addition to the debates over the potential side-effects of continuously altered senescent cell behavior versus destruction of cells that may be generating harm, but may also be propping up a tissue's structure. For example, what happens when destroying senescent cells broadly in an individual with severe atherosclerotic plaques in which a sizable fraction of cells are senescent? These debates are so far largely conducted in the absence of firm data, and that will likely continue to be the case until both approaches are more widely used in humans.

Senomorphic agents: Multi-target strategies to tame the senescence-associated secretory phenotype for healthy ageing

Cellular senescence serves as a pivotal driver of organismal ageing and its associated pathologies. This detrimental effect is primarily mediated through the secretion of a complex mixture of inflammatory factors, proteases, and other bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP), which promotes the onset and progression of multiple age-related diseases. Targeting this pathological process, the field of senotherapeutics has recently evolved two principal strategies: senolytics and senomorphic agents.

Senomorphic agents have emerged as a complementary or alternative strategy with distinct advantages. The core principle of this approach is to modulate, rather than eliminate, the function of senescent cells. By inhibiting key signaling pathways such as NF-κB, mTOR, and JAK/STAT, senomorphic agents directly curb the production of the deleterious SASP. This strategy may attenuate inflammation and tissue damage while potentially preserving certain physiological functions of senescent cells. However, the optimal balance between senolytic "clearance" and senomorphic "modulation" remains undefined, and the translational path for both strategies is fraught with challenges that have not been systematically addressed in the literature.

The present review offers three distinctive perspectives. First, we conceptualize the SASP-regulatory network as a hierarchical architecture - from upstream stress sensors to downstream epigenetic effectors - providing a systematic framework for understanding where and how senomorphic agents intervene. This framework is novel in that no prior review has explicitly organized the SASP-regulatory pathways into functional layers. Second, we critically analyze the translational barriers that have received insufficient attention in the existing literature, including the limitations of animal models, the lack of gerodiagnostic biomarkers, and the challenges of tissue-specific delivery. Third, we propose a disease-stage-adapted strategy that integrates senomorphic modulation with senolytic clearance, moving beyond the "either-or" debate toward a synergistic, precision-based paradigm. By bridging mechanistic insights with translational realities, this review aims not only to summarize the current state of the field but also to chart a roadmap for future clinical development of senomorphic therapies.

A number of prevalent age-related conditions are notably different in timing and progression between the sexes. No doubt the list of differences by sex will grow as the research community explores the first therapies that target important mechanisms of aging. Here, researchers report on an attempt to treat intervertebral disc degeneration in mice using a senolytic drug that selectively destroys the BCL-2 and BCL-xL proteins that a senescent cell needs in order to resist programmed cell death. There is a reasonable weight of evidence to point to senescent cell accumulation as an important contribution to intervertebral disc degeneration, but the outcomes here are somewhat less than hoped. Male mice suffer a greater level of pathology from the condition in this model, but also benefit to a greater degree from the senolytic therapy. BCL-2 and BCL-xL may not be the best targets for removal of senescent cells in this condition, or alternatively, the burden of senescence in this condition may be different in character or degree by sex.

The senolytic PROTAC (753b) eliminates senescent cells (SnCs) by targeting ubiquitin-mediated destruction of the anti-apoptotic BCL-2/BCL-xL proteins. Here, systemic treatment with 753b was tested for reduction of age-related intervertebral disc degeneration (IDD) in mice. Five aging male and female mice were intraperitoneally injected with 753b or vehicle between 16 and 22 months of age. Among vehicle controls, intervertebral disc (IVD) histology using Safranin-O/Fast Green staining of paraffin embedded transverse sections revealed significantly greater IDD in 22 month old males than age-matched females.

In 22-month-old males, 753b treatment significantly reduced matrix metalloproteinase (MMP)-mediated aggrecan proteolysis as shown by Western blots, loss of disc matrix aggrecan by immunohistochemistry, age-related histomorphologic features of IDD, and serum protein levels of IL-6 and TNFα protein in treated male mice. While expression of IVD cellular senescence markers IL-6, IL-8, TNFα and p16INK4a assessed by RT-PCR of IVD tissue increased with age in both 22 month old female and male mice, expression of these markers was not reduced by 753b treatment.

These results demonstrate that 753b treatment of aging mice reduced IDD in males but not females, which suggests sex-based differences in the role of senescence in IDD and may have an impact on the potential for females to benefit from anti-senescent therapies for IDD. The observed therapeutic effects of 753b on IVDs of the male mice suggest a global reduction of cellular senescence burden through systemic, non-cell autonomous processes.

Link: https://doi.org/10.18632/aging.206394

Cerebrospinal fluid drainage from the brain into the body is necessary to remove metabolic waste from the brain. The flow declines with age, and evidence strongly suggests that this is an important contribution to the build up of protein aggregates and other waste that drive the onset and development of neurodegenerative conditions. Much of the focus is on the glymphatic system of vessels at the base of the brain, but because Alzheimer's disease starts in the olfactory bulb region of the brain, a few researchers have focused on drainage through openings in the cribriform plate stucture located behind the nose. Restoring passage of cerebrospinal fluid through the cribriform plate via surgical intervention is the task undertaken by Leucadia Therapeutics, for example. Here, researchers further explore that drainage path to find other potential blockages that occur between the olfactory bulb and cribriform plate, and that may also need to be dealt with.

Researchers discovered microscopic openings in the arachnoid membrane, which they named "arachnoid fenestrations", that allow cerebrospinal fluid to pass directly into meningeal lymphatic vessels. The findings reveal the most detailed pathway yet for brain waste clearance and identify a drainage route that progressively deteriorates during aging but can be functionally restored in aged mice. The researchers identified a specialized lymphatic network located between the olfactory bulbs and the cribriform plate, the perforated bone separating the brain from the nasal cavity. Unlike other regions of the arachnoid membrane, this area contained numerous microscopic openings measuring approximately 2 to 12 micrometers in diameter.

Fluorescent tracers injected into the cerebrospinal fluid accumulated around these openings, crossed the arachnoid barrier, entered meningeal lymphatic vessels, traversed the cribriform plate, and continued through lymphatic vessels in the nasal mucosa before draining into cervical lymph nodes. Similar arachnoid fenestrations were also identified in cynomolgus monkeys, suggesting that this specialized drainage structure is conserved beyond mice. To determine whether these openings were essential for CSF drainage, the researchers physically blocked them using microspheres too large to pass through the fenestrations. This dramatically reduced cerebrospinal fluid drainage to cervical lymph nodes, providing direct functional evidence that the fenestrations serve as critical exit portals for CSF.

Instead of delivering treatment by penetrating the meninges, the membrane that cover the brain, the team administered an adeno-associated viral vector expressing vascular endothelial growth factor-C (VEGF-C) through the nasal cavity. VEGF-C is a signaling molecule that promotes lymphatic vessel growth. This less invasive intranasal approach selectively expanded lymphatic vessels surrounding the olfactory bulbs and within the nasal mucosa. Although it did not restore the age-related loss of arachnoid fenestrations or enlargement of the cribriform plate openings, the expanded lymphatic network restored cerebrospinal fluid drainage in aged mice to levels comparable to those observed in young animals.

Link: https://www.eurekalert.org/news-releases/1137060

Senescent cells accumulate with age in tissues throughout the body. These cells cease replication and secrete a potent mix of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained over the long term. Cells become senescent throughout life in response to various circumstances, but in youth are efficiently destroyed by the immune system. With old age, the immune system falters in this task for reasons that are still being explored in detail. While the increased damage and disarray found in aged cells and tissues likely accelerates the pace at which cells become senescent, present evidence suggests that immune dysfunction in the matter of senescent cell clearance is the dominant factor in the increased presence of lingering senescent cells in later life.

Various approaches to selectively removing senescent cells from aged tissues have been demonstrated in animal studies, such as the first generation of senolytic drugs (including the combination of dasatinib and quercetin) that sabotage mechanisms that senescent cells use to resist programmed cell death. A number of the biotech companies founded to develop senolytic drugs are focused instead on immunotherapies, ways to adjust the behavior of the immune system so that it can better target senescent cells for destruction. Today's scientific paper reports a novel basis for anti-senescence immunotherapy, based on removing an impediment to the ability of macrophages to destroy senescent neutrophils. Beyond the novel senolytic approach, the work is interesting for demonstrating that senescent neutrophils in and of themselves make up a sizable fraction of the entire problem of cellular senescence, at least in the liver and heart.

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear. Tissue-resident macrophages (TRMs), long-lived cells that comprise 60 to 90% of macrophages in major organs, maintain homeostasis through efferocytosis of apoptotic and senescent cells. Neutrophils, the most abundantly produced and shortest-lived leukocytes (more than 100 billion generated daily in humans), require continuous TRM clearance; uncleared aged neutrophils release proteases and extracellular traps that damage tissues and propagate aging. TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging. Whether impaired TRM efferocytosis drives the accumulation of senescent neutrophils that promote organ aging and whether inhibition of EP2 signaling can restore this process, remain unknown.

In aged mice, TRM-specific EP2 deletion restored mitochondrial fitness and immune homeostasis, and reversed cognitive decline, frailty, sarcopenia, adiposity, and cardiac dysfunction toward youthful states. Plasma proteomics identified the liver as a major source of age-associated immune changes. Single-cell RNA-seq of mouse liver and multiorgan flow cytometry revealed accumulation of senescent CXCR4+ neutrophils across efferocytic organs in aging. These cells exhibited the senescence-associated secretory phenotype (SASP), DNA damage response activation, cell cycle inhibitor induction, NETosis, and anti-apoptosis programs, and were efficiently cleared following EP2 deletion.

Liver multiplex imaging localized paracrine stress to parenchymal cells neighboring senescent neutrophils. Ex vivo efferocytosis assays showed that aged TRMs were most impaired in clearing senescent neutrophils relative to apoptotic substrates, with both functions restored by EP2 deletion or pharmacologic antagonism. Mechanistically, EP2 signaling suppressed integrin-dependent stabilization of senescent neutrophils on TRMs and downstream engulfment. Analyses of human liver and heart datasets revealed conserved EP2 up-regulation in aged TRMs, enrichment of senescent neutrophils, and reduced TRM-neutrophil interactions.

This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration. With age, neutrophils acquire senescence-associated features, and their accumulation drives tissue injury through two converging mechanisms: intrinsic degranulation and NETosis, and extrinsic paracrine stress on neighboring parenchymal cells. Pharmacological inhibition of EP2 restores TRM efferocytic capacity and promotes clearance of senescent neutrophils, positioning EP2 antagonism as a tractable therapeutic strategy for age-related organ and functional decline.

Microglia are innate immune cells of the brain, very similar to the macrophages found elsewhere in the body outside the central nervous system. Both microglia and macrophages do much more than defend against pathogens; both are deeply involved in tissue maintenance, function, and regeneration. It is by now well established that microglia become inappropriately inflammatory in old age, and researchers increasingly see this as an important component of age-related neurodegeneration. Here, researchers present provocative data to argue that the microglia of old age are not the same cell type as the microglia of youth; they are instead more like macrophages, derived from circulating monocytes outside the brain. This is a sizable departure from the present understanding, a wrench thrown into the works for several possible therapeutic approaches to microglial dysfunction in old age, so one should probably wait for confirmation before taking it at face value.

Prior studies have identified age-related shifts in gene expression, including increased inflammatory signaling and reduced synaptic function, implicating transcriptional dysregulation in brain aging. However, gene expression alone provides an incomplete view. To address this, we profiled gene expression and multiple layers of epigenetic regulation, including chromatin accessibility, DNA methylation, and three-dimensional (3D) genome organization at single-cell resolution across the adult lifespan.

Aging is associated with coordinated and often nonlinear changes in gene regulation across cell types, with a major transition occurring around midlife. A notable finding was a remodeling of the brain's immune cell landscape. Microglia underwent a nonlinear transition in which embryonically derived, brain-resident microglial cells were progressively replaced by a population with epigenetic features resembling blood-circulating monocytes. This transition was not readily detectable using gene expression alone but was revealed by DNA methylation, which preserves cellular lineage. These monocyte-like microglia exhibited epigenetic, transcriptional, and 3D genome features associated with proinflammatory programs, suggesting a potential driver of age-related neuroinflammation.

Link: https://doi.org/10.1126/science.adt8307

Atrial fibrillation is a disruption of normal heart rhythm. It becomes more prevalent with old age, and at its most severe end can contribute to cardiovascular mortality. Much of the incidence of atrial fibrillation is idiopathic, meaning the cause is obscure. Treatment tends to focus on the more severe cases and surgery to map the electrical connections in the heart and ablate regions that are causing issues, regardless of the underlying reasons as to why those regions might cause issues. Research suggests that the gut microbiome may play a role in idiopathic atrial fibrillation via generation of the metabolite TMAO, which is disruptive to the regulation of heart rhythm. Some people with idiopathic atrial fibrillation may be able to eliminate or dampen the severity of episodes by suitably altering their diet and thus adjusting the behavior and composition of the gut microbiome. A number of potential strategies for pharmaceutical inhibition of TMAO production exist, such as use of iodomethylcholine, but none of these compounds have been developed as drugs.

Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5,090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7).

Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice. Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline to TMA(O) metabolic transformation, reduced circulating TMAO levels and choline induced AF onset.

Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.

Link: https://doi.org/10.1172/JCI201684

Cancer is a dark mirror to the normal processes of tissue maintenance, in which normally helpful processes run amok and become pathological when harnessed to make tumors grow. A cancer is a subversion of normal regeneration and maintenance. Aging, on the other hand, is a progressive disruptive failure of those same mechanisms of regeneration and maintenance. Thus many of the issues found in aging are also of interest to the cancer research community, and have been studied in that context for considerably longer than the modern longevity biotechnology community has existed. It is quite common to find that an existing class of drug that might be of interest in the context of aging was initially developed as a cancer therapy.

T cell exhaustion is a feature of aging. These adaptive immune cells become unresponsive and do not contribute to immune defense as they should. T cell exhaustion is also a well known feature of cancer, one of the ways in which the immune system falls short in its ability to destroy a growing tumor. T cell exhaustion also hinders the deployment of immunotherapies that depend on the immune system's anti-cancer capabilities. Immune cells engineered to attack a cancer and introduced into the patient as a therapy often burn out and become exhausted long before they can make a meaningful dent in the size of a tumor, a faster and more exaggerated version of what happens to native, unmodified immune cells.

Today's research materials discuss what happens under the hood in the exhaustion of T cells, and point to a regulator that can adjust the balance of activity versus exhaustion. Exhaustion of T cells is a metabolic collapse, the T cell has exhausted its supply of energy by conducting the energetically expensive process of making cytotoxic proteins to kill cancerous cells. The pace at which this weapons manufacture progresses determines whether the T cell can sustain its activity over time, or whether it will quickly become exhausted. Some cancers can be overcome by a short period of aggressive attacks by highly active T cells, but in other cases that is not enough, a longer period of lower intensity anti-cancer activity would produce better results.

New Strategy Could Prevent T Cell Exhaustion and Boost Immunotherapy

A major pillar of cancer immunotherapy involves stimulating T cells, the specialized killers of the immune system, to attack tumors. But this strategy has been undermined by the tendency of T cells to tire out before finishing the job. When the cells reach the fatigued stage - called T cell exhaustion - these immune cells lose the ability to sustain the attack and keep cancer growth under control. T cells enter the exhausted state to save themselves. They stop fighting to avoid becoming overstimulated and dying. When a T cell is in attack mode and making cytotoxic proteins, the mitochondria must convert nutrients from food into adenosine triphosphate (ATP). ATP is the primary molecule used by all living cells to store and transfer energy.

Researchers have now identified a signaling molecule called MEK that plays a key role in T cell exhaustion. "Think of ATP as the currency in a fund that the cell spends down. If you spend ATP on one thing, you don't have enough to do something else. The exhaustion program is a sign that the cell's bank account is getting close to zero. MEK tells exhausted cells whether to conserve fuel or go for broke. What we found is that inhibiting MEK makes the cells more conservative - helping them live longer while reducing the rate at which they produce the proteins that actually kill cancer cells." So MEK is both the problem and part of the solution - it keeps T cells at full power but risks complete burnout. This means blocking MEK is a double-edged sword: It weakens the attack but keeps the soldiers alive.

MEK inhibitors could be used selectively to rev up T cells. Patients with large tumors or a small number of immune cells are unlikely to have a strong enough response to immunotherapy to finish off the tumor quickly. In those cases, a MEK inhibitor-induced slow burn - even in an exhausted state - allows T cells to persist, which is essential when when either the task at hand (the tumor) is large or the workforce (the number of T cells) is small.

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion.

Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.

Clonal hematopoiesis of indeterminate potential (CHIP) is arguably the most studied form of somatic mosaicism, in which stem cells accumulate mutations over time, and thus patterns of those mutations spread out into the tissue supported by those stem cells. In this case, the "tissue" is the immune system, made up of immune cells descended from the hematopoietic stem cell population that is resident in the bone marrow. There is evidence for CHIP to contribute to forms of age-related disease and aspects of aging more generally, which is an argument for somatic mosaicism in all tissues to contribute to degenerative aging.

Aging is associated with organ and tissue function deterioration and consequent increased risk of disease occurrence and mortality. Recent scientific advancements have succeeded in increasing the human life span and attempts are being made to enhance the longevity further. This stretched longevity exposes the organism to increased cellular stress and accumulation of DNA damage. Mutations in leukemia-associated driver oncogenes like DNMT3A, TET2, ASXL1, TP53, PPM1D, SF3B1, SRSF2, and IDH1/IDH2, provide selective growth advantage to the mutated clones over normal hematopoietic stem cells (HSCs). Altered bone marrow (BM) microenvironment and increased pro-inflammatory milieu further accelerates the clonal expansion and eventually reduces the hematopoietic heterogeneity.

Significant increase in clonal hematopoiesis with more than two percent of peripheral blood cells arising from single hematopoietic clone is termed as clonal hematopoiesis of indeterminate potential (CHIP). CHIP is increasingly recognized as an age-associated risk factor linked to cardiovascular and neurological disorders. While epidemiological and experimental studies suggest mechanistic involvement of inflammation, current human evidence primarily supports risk association rather than definitive causality, which may vary across mutation types. Here, we have discussed the intrinsic and extrinsic changes occurring in the hematopoietic system and its role in enhancing the clonal expansion during aging. We have further discussed the role of CHIP in various diseases and diagnostic tools being currently used for CHIP diagnosis. Finally, we also discuss the current CHIP management strategies and global status of CHIP related research.

Link: https://doi.org/10.21037/atm-2026-1-0030

The vessels of the glymphatic system run parallel to blood vessels entering the brain. Glymphatic vessels provide a path for drainage of cerebrospinal fluid into the body. This is a way to remove metabolic waste from the brain, such as the protein aggregates that contribute to neurodegenerative conditions. Loss of glymphatic flow is a feature of aging, allowing the build up of metabolic waste in the brain and consequent cellular dysfunction. Researchers here report on interesting results from a relatively simple approach to restore a greater drainage of cerebrospinal fluid through the glymphatic system, intermittently changing gas levels known to affect blood vessel contraction and dilation in order to encourage fluid flow in the glymphatic system close to those vessels. It remains to be seen as to whether this will affect disease progress, but animal studies of other ways to increase drainage of cerebrospinal fluid are encouraging.

A unifying feature of neurodegenerative conditions is the accumulation of unwanted proteins in the brain. For Alzheimer's disease it is amyloid beta and Tau proteins, while for Parkinson's disease it is alpha synuclein. Related conditions such as Lewy body dementia have a similar protein buildup. Normally, the body can clear these proteins, which are often the waste products of neuron activity, using a natural process called glymphatic clearance, which takes place when our bodies enter deep sleep.

During this process, the brain tells cerebral blood vessels to dilate and constrict, which allows the cerebrospinal fluid that surrounds the brain to flow deeper into the tissue as interstitial fluid. A cycle of blood vessel dilation and contraction pumps the interstitial fluid through the brain and then back out, flushing potentially harmful proteins, inflammatory mediators, and waste into the blood so the body can clear them out. This process takes place at night, when it will not impact more complex synaptic function, which is also when the brain's neurons dump out their waste products. Indeed, many scientists believe glymphatic clearance is one of the reasons we need to sleep in the first place.

In a study conducted with 30 patients with Parkinson's disease and 33 healthy controls, researchers used MRI brain scans during sleep to figure out the frequency of oscillation between blood vessel dilation and contraction during glymphatic clearance. They then had study participants breathe in a mixture of 5% carbon dioxide (CO2) and normal air, alternating with normal room air every 35-seconds. After just one half-hour session of the new treatment, the researchers detected higher concentrations of proteins such as beta amyloid, alpha synclein, and other byproducts of brain activity in the blood, indicating these waste products had been flushed out of the brain and into the blood, allowing the body to clear them.

If lowering the CO2 levels in blood constricts the vessels in the brain, the opposite could also be true. Increasing CO2 levels could cause the vessels to dilate, and alternating raising and lowering the CO2 level would generate the pumping action needed to propel the interstitial fluid across the brain.

Link: https://www.research.va.gov/currents/0426-Exciting-new-treatment-being-developed-for-Parkinsons-Alzheimers.cfm

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