Fight Aging!

Cells become senescent constantly throughout the body and throughout life, near all as the result of reaching the Hayflick limit on replication, but also due to excessive cell stress, damage, or a toxic environment. A senescent cell ceases replication, enlarges, and secretes a pro-inflammatory, pro-growth mix of signals that attracts the attention of the immune system. In youth senescent cells are efficiently destroyed by the immune system, but this clearance slows down with age. Senescent cells thus accumulate in later life to cause chronic inflammation and disruption to tissue structure and function. The immune system also accumulates senescent cells, and researchers here investigate the epigenetic regulation of gene expression in these cells, with an eye to finding ways to reduce the burden of senescence in these populations.

The age-associated accumulation of senescent cells in tissues is one of the driving causes of aging and age-related disease. Although senescent cells secrete chemokines that facilitate the recruitment of cytotoxic immune cells for their elimination, senescent cells accumulate systemically with advancing age, suggesting that immune cell-mediated elimination of senescent cells becomes impaired with age. Recent evidence highlights a dysfunctional adaptive immune system as a potential cause for the age-associated accumulation in senescent cells. In older humans, both CD4+ and CD8+ T cells acquire features of senescence, which is linked to defective immune responses. However, the gene regulatory mechanisms that promote senescence of CD8+ T cells in aging humans, as well as the contribution of senescent CD8+ T cells to disease, remain poorly understood.

We defined and validated the transcription factor (TF) networks that control the senescence program in CD8+ T cells of a cohort of younger and older donors. One key finding of our study is that the acquisition of senescence is the main driver of epigenomic and gene expression dynamics of CD8+ T cells, with a minor contribution of chronological age. The transition to the senescence state is a major event in the epigenetic life of CD8+ T cells, as it involves the differential expression of 40% of all detectable TFs. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells.

Link: https://doi.org/10.1016/j.celrep.2025.116795

Much of the research into TGF-β signaling show that raised circulating levels of TGF-β drive chronic inflammation and related dysfunctions. Researchers have shown that reducing TGF-β levels can be used to improve health and extend life in mice, for example. Yet nothing is simple and straightforward when it comes to cellular biochemistry. Here, researchers provide evidence for a beneficial function of TGF-β, in that its presence restrains the inflammatory activity of the innate immune cells known as microglia to better preserve myelin structure in the aged spinal cord.

Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. Here, by examining spinal cord white matter tracts in mice, we determined that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of transforming growth factor beta (TGF)β signaling.

Disrupting TGFβ signaling in microglia led to unrestrained microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. Single-nucleus RNA-sequencing analyses revealed the emergence of a TGFβ signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both of which were spatially restricted to the DC. We further discovered that microglia rely on a TGFβ autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGFβ signaling is crucial for maintaining microglial resilience to myelin degeneration in the DC during aging. This highlights a previously unresolved checkpoint mechanism of TGFβ signaling with regional specificity and spatially restricted microglia-oligodendrocyte interactions.

Link: https://doi.org/10.1038/s41593-025-02161-4

The article I'll point out today manages to capture much of the gist of the present state of interactions between two opposing viewpoints on aging: firstly that aging is the consequence of an accumulation of cell and tissue damage, a byproduct of evolutionary focus on early life success, and secondly that aging is an evolved program in its entirety. In essence, the trend is now towards some form of synthesis of these two viewpoints, that the panoply of mechanisms making up degenerative aging contain something of both stochastic damage and programmed functions. One might look at the present state of the hyperfunction theory of aging as an at times confusing and contradictory effort to produce such a synthesis.

At the time that these views emerged in opposition, it mattered as to which viewpoint governed the direction of research and development aimed at intervening in the aging process. If aging is damage, then identifying and repairing damage is the only viable approach likely to produce sizable gains in health. If aging is a program (that produces damage), then adjusting gene expression and the operation of metabolism is the only viable approach likely to produce sizable gains in health.

One could point to the Strategies for Engineered Negligible Senescence for a clear paradigm of damage repair (and still can, as its component parts have been demonstrated to be useful by the results of animal studies). One could point to efforts to alter epigenetic control over gene expression, and thus the operation of metabolism, as clearly falling into a paradigm of attempts to control an aging program. That division has been muddied by the discovery that DNA double strand break repair produces epigenetic aging, coupled with the development of epigenetic reprogramming as an approach to restoring youthful epigenetic patterns to aged cells. Epigenetic reprogramming would have been called an effort to alter metabolism to adjust the aging program, but thanks to new discoveries can now be thought of as a form of damage repair. The world turns, and matters change.

Why Aging Is Not Fundamentally Programmed - and Why Programming Still Matters

Theories of aging can be broadly categorized into two groups. On one hand are those that think aging is caused by accumulation of damage due to entropy and that solving aging requires repairing these damages. On the other hand are those that think aging is driven by an evolved genetic program whose function is to cause aging. They think the solution to aging is to instruct the body to fix itself by reprogramming its cells.

The latter view has become more popular lately since it was discovered that cells can be reprogrammed to become younger in most aspects, by changing their gene expression. That shift was also amplified because several early "damage theories" were framed as overly narrow single-cause explanations that failed to explain aging (the free radical theory of aging is a classic example). Reprogramming therefore started feeling like a more complete theory. Some scientists think that if we could simply rejuvenate all the cells in the body through reprogramming their gene expression, we could then rejuvenate the whole body and effectively solve aging.

A critical error in modern aging debates is thinking that aging must be caused by either damage accumulation or programming, while in fact, both factors play a strong role in aging. More accurately, aging is fundamentally caused by accumulation of damages, but it is also influenced very strongly by programming. Reprogramming is a highly promising strategy to slow down and reverse aging. The point is, we will never get close to fully reversing aging in humans without addressing damage accumulation also. Reprogramming may partially restore many cells to more youthful states, but it cannot automatically remove a great portion of structural damages such as many of those found in the extracellular matrix.

Why does exercise slow the age-related loss of bone mineral density leading to osteoporosis? Researchers here find a critical role for mechanotransduction, the sensing of physical forces placed upon a cell, such as pressure or mechanical stress. Specifically the mechanosensor Piezo1 is triggered in mesenchymal stem cells in the bone marrow, and the subsequent response of this cell population acts to reduce inflammation, reduce fat cell generation in bone marrow, and thus allow the specialized cell populations working on bone extracellular matrix structures to better maintain a healthy bone mineral density. This opens the door to the development of therapies that can mimic this effect of exercise by triggering Piezo1 or downstream pathways.

With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation.

Importantly, our findings also indicate that Piezo1 invalidation abolishes exercise-induced benefits on bone volume and marrow adiposity, suggesting that Piezo1 senses physiological mechanical stress (presumably shear stress and compressive forces) in the bone marrow to regulate BMMSC fate decision. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.

Link: https://doi.org/10.1038/s41392-025-02455-w

RNA splicing is the assembly of exons (and discarding of introns) to form a protein. Many genes contain the instructions for multiple proteins, and which protein is produced is governed by the operation of the splicing machinery. That operation is known to change with age, but the question remains open as to just how important RNA splicing is to age-related degeneration. Researchers here use a novel approach to identify genes with age-related alterations in expression that are similar in all tissues, and find that the results are biased towards RNA splicing machinery. The interesting part of the paper is the speculation in the discussion section regarding the reasons why alterations in RNA splicing activities could be important in aging, suggesting a connection to DNA damage. This line of thinking is particularly interesting given recent evidence for repeated activation of DNA repair processes to trigger the epigenetic changes characteristic of aging. Looking at DNA damage, epigenetic change, and altered alternative splicing may be three viewpoints into the same process of aging centered on the structure and function of nuclear DNA and its surrounding machineries of gene expression.

Although transcriptomic changes are known to occur with age, the extent to which these are conserved across tissues is unclear. Previous studies have identified little conservation in age-modulated genes in different tissues. Here, we sought to identify common transcriptional changes with age in humans (aged 20 to 70) across tissues using differential network analysis, assuming that differential expression analysis alone cannot detect all changes in the transcriptional landscape that occur in tissues with age. Our results demonstrate that differential connectivity analysis reveals significant transcriptional alterations that are not detected by differential expression analysis. Combining the two analyses, we identified gene sets modulated by age across all tissues that are highly enriched in terms related to "RNA splicing" and "RNA processing".

Alternative splicing is a fundamental process in eukaryotes that allows the same gene to encode multiple different transcripts, with approximately 95% of multi-exon genes producing transcripts that undergo alternative splicing. Therefore, it is intuitive that alterations in the splicing machinery would have systemic effects on the biological network. Indeed, aging appears to be accompanied by a high incidence of aberrant splicing and intron retentions. Changes in alternative splicing are also observed in several age-related diseases. Modulation of specific splicing factors has been shown to increase lifespan in model organisms, and splicing appears to be modulated in model organisms during dietary restriction and mTOR inhibition, two known lifespan-promoting interventions.

Determining the cause of this increased incidence of aberrant splicing is currently impossible. One hint is the presence of genes associated with DNA repair and DNA damage response. The idea that DNA alterations cause aging is one of the most classic theories of aging, and DNA damage is a hallmark of aging. It is possible, therefore, that damage to DNA is leading to aberrant splicing. Indeed, there seems to be a connection between RNA splicing and DNA damage response, even at the transcriptional level.

From the results described here, it is reasonable to imagine a scenario in which the age-associated increase in aberrant mRNAs, proteins, and eventually organelles, which were negatively affected by malfunctioning proteins, may impose significantly on catabolic processes such as RNA catabolism, protein catabolism, and autophagy. Lifespan extension by mTOR inhibition may thus be working by inducing the clearance of these defective components. Since these clearance mechanisms seem upregulated with age, mTOR inhibition is enhancing a naturally occurring attempt at adaptation by the cells.

Link: https://doi.org/10.18632/aging.206347

The composition of the gut microbiome changes with age in ways that harm long-term health, via growth in inflammatory species versus loss of species producing beneficial metabolites. This is well demonstrated in a range of species, including extensive human data. Presently widely available probiotic and prebiotic approaches only produce short-term adjustment in the balance of microbial popultions, but there are a few alternative approaches to adjust the gut microbiome that do produce permanent change with a single course of treatment. One of these is fecal microbiota transplantation. In animal studies, fecal microbiota transplantation from young donors to aged animals rejuvenates the composition of the gut microbiome, improves health, and extends life span.

Data suggests that some age-related conditions are associated with an altered gut microbiome, including Alzheimer's disease and Parkinson's disease. Interestingly, Parkinson's disease includes intestinal symptoms such as constipation that have motivated researchers to conduct some small trials of fecal microbiota transplantation; neurological symptoms of the condition were also improved as a result. Beyond this there is as yet little clinical evidence for effects of fecal microbiota transplantation in the context of aging. More data would be very useful, as this form of therapy is readily conducted, costs little, and certainly could be more widely used than is presently the case given a larger body of supporting evidence.

The application of fecal microbiota transplantation in Parkinson's disease

Parkinson's disease (PD) is a multisystem neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) in dopaminergic neurons of the substantia nigra. The pathogenesis of PD remains incompletely understood, and disease-modifying therapies are lacking. Emerging evidence suggests that gut microbiota and their metabolites influence both intestinal and central nervous system (CNS) functions via the microbiota-gut-brain axis (MGBA). Recent studies have identified dysbiosis in the gut microbiota of PD patients, which may contribute to disease progression through two primary mechanisms: First, increased intestinal permeability, allowing pro-inflammatory factors and microbial metabolites to affect the enteric nervous system (ENS) and subsequently spread to the CNS via the vagal neurons; Secondly, disruption of the Blood-Brain barrier (BBB), leading to neuroinflammation and aberrant α-syn aggregation, ultimately resulting in dopaminergic neuron degeneration.

Fecal microbiota transplantation (FMT) has demonstrated significant efficacy in alleviating PD-associated constipation, characterized by an increased abundance of Firmicutes and decreased proportions of Proteobacteria and Bacteroidetes in treated patients. These microbial compositional changes correlate with effective amelioration of both constipation and tremor symptoms. In 2021, a study demonstrated that FMT significantly reduces Bacteroides abundance while increasing Prevotella and Blautia populations in PD patients with constipation. These microbial alterations were associated with marked improvements in PD symptoms. Another group conducted colonoscopic infusion of donor FMT in six PD patients, demonstrating significant improvements in motor symptoms, non-motor symptoms, and constipation over a six-month observation period. In 2024 researchers conducted a nasoduodenal FMT trial involving 43 early-stage PD patients. Post-transplantation assessments revealed significant improvements in both motor symptoms and constipation compared to baseline. Notably, the study also demonstrated FMT-mediated enhancement of cognitive functions, including amelioration of anxiety, depressive symptoms, and sleep disturbances.

Sensors such as cGAS in the cell evolved to detect invading pathogens and then interact with inflammatory regulators such as STING to produce an appropriate response. With age, however, many of the dysfunctions that arise in a cell can produce a maladaptive response on the part of cGAS and STING. The example noted here is the activation of dormant transposons in the genome, a feature of aging that emerges as epigenetic control over the structure of nuclear DNA and expression of nuclear genes changes for the worse. Retrotransposons like LINE-1 make up a sizable fraction of the genome as a result of their ability to copy themselves. They are most likely the remnants of ancient viral infections, important in aging as they become active, and likely important as a source of evolutionary change to genetic sequences as well. Retrotransposons can cause harm not just by damaging the genome as they copy themselves, but also via inflammatory reactions on the part of cGAS, STING, and other mechanisms evolved to react to anything that looks like viral machinery.

Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice.

Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with established brain aging biomarkers, including neurofilament light chain (NFL). Utilizing mouse models, we demonstrate that EVs from aged individuals penetrate the blood-brain barrier, deliver LINE-1 RNA to microglia, and initiate cGAS-STING signaling, leading to pronounced neuroinflammation, neuronal damage, and impaired cognition.

Pharmacological blockade of LINE-1 reverse transcription by 3TC or inhibition of STING signaling with H151 significantly ameliorates these age-associated deficits. Notably, aged peripheral tissues, especially brain and lung, emerge as primary sources of pro-aging EVs enriched with LINE-1 RNA, revealing a novel mechanism of inter-organ communication in aging. Our findings position EV-derived LINE-1 RNA and its downstream cGAS-STING pathway as critical systemic drivers of brain aging, presenting promising therapeutic targets for mitigating cognitive decline and age-related neurodegenerative diseases.

Link: https://doi.org/10.1111/acel.70350

Researchers here discuss what is known of the bidirectional relationship between the aging of skeletal muscle and the aging of the gut microbiome. Muscle tissue is metabolically active, generating myokine signals influential on other tissues. This signaling is far from fully mapped, but is known to be important to health, such as via mediating some of the benefits of exercise. Myokine signaling can also affect the composition of the gut microbiome. In turn, changes in the gut microbiome can contribute to the characteristic loss of muscle mass and strength that takes place with advancing age via increased inflammatory signaling or reduced generation of beneficial metabolites known influence muscle metabolism, such as butyrate.

The interplay between gut microbiota and sarcopenia has emerged as a cutting-edge research topic in the medical field, garnering significant attention. Sarcopenia is an age-related syndrome characterized by a progressive decline in skeletal muscle mass, strength, and function, which profoundly impacts the quality of life in older adults and imposes substantial socioeconomic burdens on many counties. Accumulating evidence indicates that alterations in the gut microbiota are not only linked to various intestinal disorders but also to aging-associated conditions, such as sarcopenia.

The gut microbiota plays a pivotal role in regulating skeletal muscle homeostasis via its metabolic products and is increasingly recognized as a potential pathophysiological factor contributing to sarcopenia development. Skeletal muscle, functioning as both a motor and endocrine organ, secretes myokines that exert critical regulatory effects on the gut microbiota. In sarcopenic individuals, reduced secretion of myokines correlates with decreased microbial diversity and compositional shifts, marked by diminished beneficial microbes and increased potentially harmful species. This establishes a vicious cycle of gut dysbiosis-sarcopenia-gut dysbiosis.

Modulation of the gut microbiota has been demonstrated to enhance muscle mass and function in elderly patients with sarcopenia. Metabolites derived from the gut microbiota, such as amino acids, lipopolysaccharides, and short-chain fatty acids, are known to modulate skeletal muscle protein metabolism by influencing anabolic and catabolic pathways. Nevertheless, the bidirectional mechanisms underlying the relationship between gut microbiota and age-related sarcopenia remain incompletely understood.

Link: https://doi.org/10.3389/fmicb.2025.1638880

Calcification of tissues involves the inappropriate deposition of calcium structures. It is a feature of aging in the cardiovascular system particularly, where calcification contributes to stiffening and dysfunction of tissues. Calcification proceeds alongside the development of atherosclerotic plaque, and thus has long been used as a marker to assess the extent of atherosclerotic cardiovascular disease, but it is a distinct mechanism and pathology. Two people with the same degree of vascular thickening and plaque development can have quite different degrees of calcification.

At the present time there is little that can be done about calcification of blood vessel walls and structures of the heart. As for many aspects of aging, there is evidence for some approaches to be able to modestly slow the progression of calcification, but means of robust and sizable reversal of calcification have yet to be developed. The best widely available approach achieved to date is EDTA chelation therapy, and this is nowhere near as effective or reliable as one might hope it to be.

In today's open access paper, researchers discuss the role of sirtuins in the mechanisms thought to be involved in modest slowing of vascular calcification. The primary point of focus is the long-standing antidiabetic drug metformin, and thus much of the data is derived from diabetic patients and mice. The likely effect sizes are small, and may be more relevant to a diabetic aging metabolism than to a normal aging metabolism. All in all, this is of more academic interest to those following the ongoing story of research into sirtuins than it is of relevance to efforts to treat aging as a medical condition.

Mechanism and treatment of Sirtuin family in vascular calcification

The SIRT family has shown potential in alleviating vascular aging by inhibiting inflammation, reducing endoplasmic reticulum stress, lowering mitochondrial oxidative stress, and promoting DNA damage repair, all of which contribute to the suppression of vascular calcification. Notably, SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have demonstrated therapeutic potential in the treatment of vascular calcification (VC). The occurrence of VC involves the participation of multiple factors, primarily attributed to the abnormal deposition of calcium and phosphorus in the vascular wall. This article primarily discusses how the SIRT family can ameliorate VC through various.

Recently, some studies have confirmed that ferroptosis can promote VC, indicating that metformin may alleviate the development of hyperlipidemia-associated VC by inhibiting ferroptosis. Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation, regulated by multiple pathways, including redox balance, lipid metabolism, and energy metabolism. Metformin enhances autophagy and inhibits abnormal cell proliferation through the AMPK/SIRT1-FoxO1 pathway, thereby mitigating oxidative stress in diabetic nephropathy. Previous studies have demonstrated that metformin can increase the expression of SIRT3 and GPX4, significantly elevate the levels of phosphorylated mTOR and phosphorylated AMPK, and improve polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.

SIRT proteins may serve as crucial intermediates for metformin's inhibition of ferroptosis-related vascular calcification. They play a synergistic role by regulating the antioxidant system, iron metabolism, and cellular phenotype transformation. Future research should concentrate on specific activation strategies for SIRT proteins, such as selective agonists, to enhance the targeted therapeutic effects of metformin.

Hesperidin has been shown to prevent the development of calcific aortic valve disease via the SIRT7-Nrf2-ARE axis. Future studies could further investigate the SIRT family's pathways that inhibit VC through ferroptosis. Moreover, the SIRT family influences VC through various signaling pathways, including the Wnt/β-catenin, Runx2, NF-κB, and JAK/STAT pathways, as well as the AMPK signaling pathway. Additionally, the role of the SIRT family in VC is noteworthy, with current research primarily focusing on SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7, while the functions of other SIRT proteins in VC remain to be explored. Clinically, it has been observed that a significant number of patients requiring coronary intervention exhibit multiple calcifications in the vessel walls; thus, investigating methods to prevent and delay the progression of VC is a promising area for future research.

Longevity has always been a matter of interest, but absent an earnest scientific endeavor focused on intervention in aging it remained in the realm of fantasy, fraud, and futile wishes. That scientific endeavor was late in arriving, this delay largely the result of a cultural battle spanning the late 20th century that took place between the founders of modern anti-aging clinical practices and supplement industry companies on the one side versus the aging research community on the other. Only over the last thirty years has a scientific community finally emerged to earnestly and openly focus on treating aging as a medical condition.

The pursuit of youth and longevity has accompanied human societies for millennia, evolving from mythological and esoteric traditions toward a scientific understanding of aging. Early concepts such as Greek ambrosia, Taoist elixirs, and medieval "aqua vitae" reflected symbolic or spiritual interpretations. A major conceptual transition occurred between the late nineteenth and early twentieth centuries, when aging began to be framed as a biological process. Pioneering ideas by Metchnikoff, together with early and sometimes controversial attempts such as Voronoff's grafting experiments, marked the first efforts to rationalize aging scientifically. In the mid-twentieth century, discoveries including the Hayflick limit, telomere biology, oxidative stress, and mitochondrial dysfunction established gerontology as an experimental discipline.

Contemporary geroscience integrates these insights into a coherent framework linking cellular pathways to chronic disease risk. Central roles are played by nutrient-sensing networks such as mTOR, AMPK, and sirtuins, together with mitochondrial regulation, proteostasis, and cellular senescence. Interventions, including caloric restriction, fasting-mimicking diets, rapalogues, sirtuin activators, metformin, NAD+ boosters, senolytics, and antioxidant combinations such as GlyNAC, show consistent benefits across multiple model organisms, with early human trials reporting improvements in immune function, mitochondrial activity, and biomarkers of aging. Recent advances extend to epigenetic clocks, multi-omic profiling, gender-specific responses, and emerging regenerative and gene-based approaches. Overall, the evolution from historical elixirs to molecular geroscience highlights a shift toward targeting aging itself as a modifiable biological process and outlines a growing translational landscape aimed at extending healthspan and reducing age-related morbidity.

Link: https://doi.org/10.3390/molecules30244728

Aging clocks are a way to obtain a measure of the state of biological age, the burden of damage and dysfunction that causes age-related disease and mortality. A wide variety of clocks have been developed, but this technology has yet to realize its full promise, which is to be used as a standardized measure of the efficacy of potential age-slowing and age-reversing therapies. If researchers had a robust, reliable way to immediately assess the quality of a therapy, it would dramatically speed research, and focus progress on the best classes of therapies. We might ask why aging clocks have yet to provide this capacity; the article here looks at this question and what needs to be done in order to realize this goal.

What you want to do is what drives decision-making and sets the goalposts. So let's look at the intended uses for aging clocks: (1) R&D: You want to do experiments to understand biology and/or find new candidate therapies, and avoid waiting for aging and death as your readouts. (2) Consumer health optimization: You want to monitor and probability optimize your health. You'll do measurements at regular intervals, and change your behavior by whether the clock goes up or down. (3) Design and interpret clinical trials: You want to select who goes into your trial, or identify people who respond better or worse to some treatment, purely for your own learning. (4) FDA approval: You want to run a clinical trials and get Accelerated Approval from the FDA based on lowering clock scores, ahead of showing improvements in mortality or disease. (5) Medical care: You want to run tests know whether prescribed medicines and behaviors are working. Wrong results are a big deal, as they could lead to wrong treatments (and, in the US, lawsuits galore).

It's telling that today, aging clocks are frequently used for the first two purposes but approximately never for the last three (where the cost of being wrong is high). Evidently, people in charge of these costly decisions do not think that aging clocks are ready to use. Why is that? The original clocks were strictly correlated to chronological age, which is not a very useful thing to estimate. But later clocks have been trained to predict mortality, frailty, and other important outcomes. So the answer must be that we can't yet trust their predictions.

Bold research has given us a proof of concept that the aging process can be tracked with molecular measurements. We should appreciate that. And we should acknowledge that we won't benefit much from talking about clocks' potential for practical uses until we're able to properly benchmark the required performance metrics. So let's decide on the uses we think are most valuable, and make sure we build the infrastructure to track where we are now and whether we're improving. Funding such a clock assessment program is the highest leverage in longevity. Between accelerating R&D and eventually enabling human trials, good clocks are very much worth pursuing.

Link: https://norngroup.substack.com/p/do-we-have-a-useful-aging-clock

Disruption of the regulation of circadian rhythms is a known feature of aging. As for everything to do with our biochemistry, this disruption of the circadian clock is complicated. As a starting point, there isn't just one clock. The brain runs clocks, the periphery runs more clocks, and they coordinate with one another via signaling. That coordination breaks down with age, because everything breaks down with age in one way or another, as damage and dysfunction accumulates. We can also discuss whether the various clock mechanisms that sense aspects of the environment function correctly in later life, whether the appropriate signaling is still generated in the right way, whether the receptors for those signals still operate correctly to generate the appropriate cell and tissue responses, and so forth. There are many points at which normal function can be eroded as damage mounts - and it clearly is eroded in the old.

Today's open access paper presents a novel way of looking at how the disruption of the circadian clock may contribute to age-related disease, specifically the risk of neurodegenerative disease in this case. The researchers used study data on movement and heart activity to characterize individual variations in the resilience of the circadian clock to alterations in the environment. An older person who is more affected by the environment is said to have a weak clock, whereas one who is less affected by changes in the environment has a strong clock. A strong clock correlates with a lower risk of dementia. This says little about causation, of course. The same accumulating cell and tissue damage of aging may provoke weakness in the circadian clock at the same time as it contributes to neurodegeneration. That weak clocks correlate with risk of dementia may just be pointing out that people with a greater burden of damage are more impacted than those with less of a burden of damage.

Do our body clocks influence our risk of dementia?

Circadian rhythm is the body's internal clock. It regulates the 24-hour sleep-wake cycle and other body processes like hormones, digestion, and body temperature. It is guided by the brain and influenced by light exposure. With a strong circadian rhythm, the body clock aligns well with the 24-hour day, sending clear signals for body functions. People with a strong circadian rhythm tend to follow their regular times for sleeping and activity, even with schedule or season changes. With a weak circadian rhythm, light and schedule changes are more likely to disrupt the body clock. People with weaker rhythms are more likely to shift their sleep and activity times with the seasons or schedule changes.

A new study involved 2,183 people with an average age of 79 who did not have dementia at the start of the study. Researchers reviewed heart monitor data for various measures to determine circadian rhythm strength. These measures included relative amplitude, which is a measure of the difference between a person's most active and least active periods. High relative amplitude signified stronger circadian rhythms.

Researchers divided participants into three groups, comparing the high group to the low group. A total of 31 of 728 people in the high group developed dementia, compared to 106 of the 727 people in the low group. After adjusting for factors such as age, blood pressure, and heart disease, researchers found when compared to people in the high group, those in the low, weaker rhythm group had nearly 2.5 times the risk of dementia, with a 54% increased risk of dementia for every standard deviation decrease in relative amplitude.

Association Between Circadian Rest-Activity Rhythms and Incident Dementia in Older Adults

Aging is associated with changes in circadian rhythms. Rest-activity rhythms (RARs) measured using accelerometers are markers of circadian rhythms. Altered circadian rhythms may be risk factors of neurocognitive outcomes; however, results are mixed. This was a retrospective examination of data from the Atherosclerosis Risk in Communities (ARIC) study. ARIC participants who wore the a long-term continuous monitoring patch in 2016-17 for ≥3 days and were free of prevalent dementia were included. RARs were derived from investigational accelerometer data from the patch.

Of the 2,183 participants (age 79 ± 4.5 years), 176 (8%) developed dementia. The median follow-up time was 3 years, and the mean patch wear time was 12 days. After multivariable adjustment, each 1 standard deviation decrement in relative amplitude and 1-SD increment in intradaily variability were associated with 54% and 19% greater risk of dementia, respectively. Further research to determine whether circadian rhythm interventions can reduce dementia risk is warranted.

Exercise and physical fitness has been shown to reduce the predicted biological age generated by various epigenetic clocks. Researchers here provide evidence for some of this effect to be mediated by a reduction in inflammatory signaling, also well known as an outcome of exercise and physical fitness. Chronic inflammation is harmful to tissue structure and function, and is also a feature of aging and age-related disease. To the degree that long-term inflammatory signaling unrelated to injury and infection can be minimized, the results should be improved health and modestly slowed aging.

Physical activity (PA) is recognized as a cornerstone of healthy aging, yet the molecular mechanisms linking PA to biological aging remain poorly understood. DNA methylation (DNAm)-based biological aging indicators, such as PhenoAge, provide a means to assess the relationship between PA and aging at the molecular level.

β2-microglobulin (β2M) is elevated in states of chronic inflammation and is implicated in immune senescence. Elevated levels are detected in the plasma and cerebrospinal fluid of aged mice and older adults. This study analyzed data from 936 participants in the U.S. population, assessing associations between PA, β2M levels, and PhenoAge.

Our study showed that increased PA was significantly associated with lower β2M levels, and mediation analysis revealed that reductions in β2M explained 37.67% of the association between PA and PhenoAge. These results align with findings that PA mitigates inflammation by reducing pro-inflammatory cytokines and improving immune function. Importantly, the direct effect of PA on PhenoAge remained significant even after accounting for β2M, suggesting additional pathways through which PA exerts anti-aging effects, such as epigenetic regulation or mitochondrial function.

Link: https://doi.org/10.1016/j.jare.2025.11.047

Retro Biosciences was one of the more comprehensively funded companies in the longevity industry at launch, and has pursued a number of different programs. The first program to reach an initial clinical trial is a small molecule drug to upregulate autophagy, a goal pursued by a wide range of programs, most notably those focused on mTOR inhibitors and related calorie restriction mimetics. Increased autophagy should modestly slow aging, though as always the size of the effect is a guess until human data emerges - and that might take a while. Rapamycin upregulates autophagy, has long been known to do that, costs little, and we still have no idea what it does to the pace of aging in humans.

Longevity biotech Retro Biosciences has achieved its goal of becoming a clinical-stage company in 2025, after dosing the first participant in a clinical trial of its autophagy-focused drug candidate. Retro's clinical drug candidate, RTR242, is a small-molecule therapy designed to restore lysosomal function, a core component of autophagy - our cells' waste-handling and recycling system. In healthy, younger cells, lysosomes maintain an acidic environment that allows the autophagy process to break down damaged proteins and cellular debris. As people age, and particularly in neurodegenerative diseases such as Alzheimer's, lysosomes lose acidity and efficiency. The result is a buildup of toxic protein aggregates that place chronic stress on neurons and contribute to their dysfunction and eventual loss. Retro's approach aims to repair this decline at its source, reactivating the cell's own cleanup machinery rather than targeting the problem downstream.

The Phase 1 study is a randomized, double-blind, placebo-controlled trial in healthy volunteers, conducted at a specialized early-phase clinical unit in Australia. In addition to standard safety and tolerability measures, the study includes exploratory biomarkers tied to autophagy and lysosomal biology, giving Retro its first opportunity to observe whether its mechanistic hypotheses translate into measurable biological signals in humans. Failures in cellular clearance are a common feature across many degenerative conditions, so if the biology proves tractable in humans, the hope is that the approach could have applications beyond neurodegeneration, informing approaches to other disorders where accumulated cellular damage plays a central role.

Link: https://longevity.technology/news/retro-bio-commences-first-in-human-trial/

As you may know, there are significant differences in incidence and outcomes of Alzheimer's disease between the sexes. In research, differences of this nature can help in developing a better understanding of which mechanisms are more versus less important in the disease process, and so guide efforts to produce therapies. The biochemistry of the brain is enormously complex, and thus so is the pathology of Alzheimer's disease. It remains the case that decades of research cannot do any better than practical experimentation when it comes to determining which mechanisms cause the most harm. See the present focus on clearance of amyloid-β aggregates from the brain, for example. Only once the necessary immunotherapies existed could the research community determine that amyloid-β aggregates are not as important as hoped in the pathology of the condition.

The focus of today's open access paper is largely the role of inflammatory, dysfunctional microglia in Alzheimer's disease, and whether this provides a sizable contribution to sex differences in disease outcomes. The role of microglia in Alzheimer's disease is a growing area of research interest that seems likely to lead to novel therapies and initial clinical trials in the years ahead. Microglia are innate immune cells of the central nervous system, somewhat analogous to the macrophages found elsewhere in the body. In addition to attacking pathogens and destroying unwanted cells, they are also involved in regeneration and maintenance of nervous system tissue, including some of the changes to neural circuits needed for learning and memory. When microglia become overly inflammatory, it is harmful to the structure and function of the brain.

Microglial interferon signaling and Aβ plaque pathology are enhanced in female 5xFAD Alzheimer's disease mice, independent of estrous cycle stage

Alzheimer's disease (AD) presents with a sex bias in which women are at higher risk and exhibit more rapid cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether and how microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterized the sex differences in amyloid-beta (Aβ) plaque pathology and microglia-plaque interaction using the 5xFAD mouse model and revealed microglial transcriptomic changes that occur in females and males.

Despite women with symptomatic late-onset AD being in the post-menopausal stage, metabolic and pathological changes are seen prior to menopause. For this reason, and because Aβ pathology develops decades prior to clinical presentation, we focused on two hormonally distinct stages of the female rodent estrous cycle (proestrus and diestrus). Our results showed that Aβ plaque morphology is sexually distinct, with females having greater plaque volume and lower plaque compaction compared to males of the same age. Neuritic dystrophy was also increased in female 5xFAD mice, independent of estrous cycle stage. While microglia transcriptomes were not overtly different at the proestrus or diestrus stages, female 5xFAD microglia upregulated genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia, and microglia neurodegenerative phenotype compared to males, some of which have been previously reported.

In addition, we found a novel female-specific enhancement of IFN signaling in microglia, as evidenced by a striking proportion of differentially expressed type 1 interferon genes characteristic of interferon-responsive microglia (IRM). Finally, we validated our transcriptomic results at the protein level and observed that female 5xFAD mice had an enrichment in Aβ+ IRMs compared to males. Collectively, we show that there are sex-specific alterations in Aβ plaque morphology and that endogenous hormonal fluctuations across the estrous cycle do not overtly affect Aβ pathology or microglial transcriptomic profiles. Furthermore, our study identifies a novel sex-specific enhancement of interferon signaling in female microglia responding to Aβ, which may constitute a new therapeutic target for personalized medicine in AD.