Fight Aging!

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.

Cystathionine γ-lyase (CSE) levels are reduced with age, and researchers here show that removing CSE entirely in mice reproduces aspects of brain aging. That isn't enough to prove that the smaller reductions that take place with age do in fact make a meaningful contribution to neurodegeneration, but it is sufficient to justify greater attention and further research into to the mechanisms involved. The researchers chose to focus on CSE because it is involved in the production of hydrogen sulfide (H2S) in the brain. You may recall that the ability of increased H2S to be somewhat protective in the context of aging, such as via effects on inflammation and autophagy, has grown as a topic of interest in recent years. It is hard to effectively deliver H2S to the brain, however, as both normal and beneficial levels are very low; it is arguably better to try to adjust the operation of the biochemistry responsible for producing H2S instead.

Once considered to function predominantly in the peripheral systems, cystathionine γ-lyase (CSE) is emerging as a key player in neuroprotection. Prior studies had considered cystathionine β-synthase (CBS) to be the principal enzyme governing H2S signaling in the brain. In this study, through an integrated approach combining genetic, proteomic, biochemical, and behavioral studies, we demonstrate that CSE is crucial for maintaining brain homeostasis and that loss of CSE is sufficient to trigger cognitive deficits.

CSE, the enzyme responsible for neuronal cysteine and hydrogen sulfide production, is dysregulated in aging and neurodegenerative diseases including Alzheimer's disease and Huntington's disease, both marked by cognitive decline in addition to motor deficits. To determine whether CSE loss directly causes cognitive decline, we genetically ablated CSE in mice. This loss was sufficient to induce oxidative damage, compromise blood-brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits. Global proteomic analysis further revealed molecular alterations that contribute to impaired neurogenesis.

Our findings establish CSE as an essential guardian of homeostatic brain health and identify it as a potential therapeutic target for neurodegenerative disorders.

Link: https://doi.org/10.1073/pnas.2528478122

Treatment immediately following stroke is not the most obvious path to take for the clinical development of therapies intended to improve drainage of cerebrospinal fluid via the glymphatic system, but nonetheless that is the approach taken by the research program noted here. A range of compelling evidence points to age-related impairment of the drainage of cerebrospinal fluid from the brain as an important issue, but is largely focused on the slow development of neurodegenerative conditions as a result of the buildup of metabolic waste in the brain. The immediate aftermath of a stroke is a very different scenario, amenable to different approaches to improvement of drainage channels, such as the non-invasive devices proposed here that would probably be infeasible for long-term use.

The "brain-draining lymphatics" are a set of drainage pathways that clear waste from the brain, with dysfunction of this "clean-up and drainage network" linked to Alzheimer's disease and other neurological and neurodegenerative diseases (NNDs). Researchers found that improving brain-draining lymphatic function can boost recovery following ischemic stroke and are now developing non-invasive devices that help the neck's lymphatic vessels pump more effectively, improving the clearance of excess fluid and harmful waste from the brain right after stroke has occurred - at a time when every second counts.

The researchers are also using advanced imaging techniques to study the brains of 140 participants. Initial studies have found that women have less lymphatic vessel coverage in the brain's outer layer compared to men, potentially leading to less efficient waste drainage and explaining why women are at higher risk or have worse outcomes for many NNDs, including stroke and Alzheimer's disease. "The brain was considered to be devoid of a lymphatic system. It wasn't until 2015 that two separate teams discovered that lymphatics in the brain's outer layer transport fluid and waste products from the brain to lymphatic vessels in the neck. We now know that this system plays a crucial role in keeping the brain healthy. By boosting this natural clean-up system, we hope to change how ischemic stroke and other NNDs are treated."

Link: https://www.monash.edu/news/articles/scientists-unlock-brains-natural-clean-up-system-to-develop-new-treatments-for-stroke-and-other-neurological-diseases

The overt manifestations of the aging of hair follicles, going gray and losing hair, often appear to bother people to a greater degree than the impending failure of their internal organs. In principle a sufficient understanding of the mechanisms of aging should lead to ways to avoid both outcomes. Rejuvenation therapies that repair the cell and tissue damage of aging should do as much for hair as for any other part of the body. Under the hood, however, there is still the matter of the ferocious complexity of cellular biochemistry and its changes with age. A hair follicle is not like a muscle fiber or a glomular unit of the kidney or a portion of a neural network in the brain. These are all made of cells, but completely different in the details of their responses to the damage that is characteristic of aging.

As illustrated by the fact that effective therapies to address hair aging do not yet exist, the research community does not fully understand the ways in which the processes of hair growth and coloration run awry with age. Hair growth is quite complex. It is not a continuous process, but one that proceeds in phases of communication between cells of various types that make up a hair follicle. Different cells do different things at different times and in different locations in the follicle - and this can all be impaired in any number of ways. In response to this sort of challenge, the research community settles into a mode of gathering ever more detailed data, in search of patterns that might lead towards greater understanding and points of intervention.

Single-cell RNA sequencing profiles age-related transcriptional landscapes in human hair follicle cells

Hair loss and graying, the earliest visible signs of skin aging, are driven by the functional decline of hair follicle stem cells and their niches. To elucidate the transcriptional mechanisms involved in scalp aging, we conducted a comprehensive analysis of human scalp samples using single-cell RNA sequencing and spatial transcriptomic technologies. Our study profiled the transcriptomes of 57,181 cells from scalp samples obtained from four young, six middle-aged, and one elderly individual. The integrated bioinformatic pipeline included cell clustering, spatial deconvolution, pseudotime trajectory, as well as cell-type specific gene expression, and intercellular communication analysis. An additional 92 volunteers were included, comprising 90 (37 young, 27 middle-aged, and 26 elderly) for trichoscopic examination, one young individual for senescence-associated β-galactosidase (SA-β-gal) staining, and one elderly individual for both MKI67 immunofluorescence and SA-β-gal staining.

This approach led to several key findings: we identified three subtypes of mitotic keratinocytes that localized in the interfollicular epidermis (IFE), outer root sheath (ORS), and hair matrix, with pseudotime trajectory further confirming their transitional stage. Furthermore, in middle-aged scalps, we observed activated activator protein 1 (AP-1) transcription factor complex in keratinocytes, upregulated DCT gene in melanocytes, and decreased bone morphogenetic protein (BMP) and noncanonical wingless/integrated (ncWNT) signaling in dermal papilla (DP)-keratinocytes cross-talk.

In the age-associated analysis of single-cell transcriptomics, AP-1 activation emerged as a hallmark of middle-aged hair follicle and epidermal cells, consistent with its known role in chromatin remodeling and senescence-associated transcriptional reprogramming. The downstream targets of AP-1 - such as MYC, SOCS3, DUSP1, NR4A1, and NFKBIA - form an intricate regulatory network that influences cell cycle progression, inflammatory responses, and stem cell depletion. This coordinated regulation reflects a dynamic cellular strategy in aging skin - balancing stem cell activation and stress adaptation while restraining excessive proliferative and inflammatory signaling to maintain tissue homeostasis. In addition, DCT was upregulated in melanocytes in the middle-age group, suggesting overactive melanin synthesis caused by inflammaging. Future studies leveraging in vivo and in vitro human hair follicle models are essential to elucidate the causal role of this AP-1-centered network and to evaluate whether targeting AP-1 or its downstream pathways could delay stem cell depletion and offer novel therapeutic avenues for age-related hair loss and graying.

Any broad consideration of exosomes is entirely too broad to fit in one paper. Exosomes are one category of extracellular vesicles, membrane-wrapped packages of molecules released by cells as a part of cell to cell communication. At this point the diversity of extracellular vesicles and circumstances leading to their generation and selection of specific contents are not well mapped, but nonetheless one major component of ongoing research is to establish sources of exosomes or other vesicles that can be used as a basis for therapy. It is well understood at this point that the benefits of stem cell transplantation emerge from the signals produced by the transplanted cells in the short time they survive. Harvesting extracellular vesicles from stem cells in culture and then infusing these vesicles instead of the cells produces similar outcomes in preclinical studies, but is logistically easier to manage. Developers are moving towards formal clinical trials, while extracellular vesicle treatments are already widely available via medical tourism and other avenues.

Aging is accompanied by a gradual decline in physiological resilience and an increased risk of chronic diseases collectively known as age-related disorders, including neurodegeneration, cardiovascular disease, and osteoarthritis. Exosomes, nano-sized extracellular vesicles, have emerged as critical mediators in the aging process and related pathologies. By moving bioactive cargo such as proteins, lipids, and mRNAs exosomes facilitate intercellular communication and modulate processes central to aging, including inflammation, immune response, senescence, and tissue repair.

Exosomes contribute to "inflamm-aging," influence stem cell function, and reflect age-associated molecular alterations, positioning them as potential biomarkers for early diagnosis and disease monitoring. Understanding dual role of exosomes as both contributors to aging and platforms for intervention offers new avenues for promoting healthy longevity and mitigating the burden of age-associated diseases. Also, their inherent stability, low immunogenicity, and capacity for targeted delivery make exosomes promising candidates for therapeutic applications in regenerative medicine and anti-aging interventions.

This review synthesizes current knowledge on exosome biogenesis, composition, and functional roles in aging and age-related diseases. We discuss emerging evidence supporting their use as diagnostic and prognostic tools and their potential in cell-free therapies aimed at modulating age-related decline. Despite their promise, several challenges impede clinical applications. Addressing these limitations will be essential to fully harnessing the therapeutic potential of exosomes in aging. Notwithstanding these obstacles, exosomes exhibit significant potential for personalized and combinatorial therapies. Understanding the dual role of exosomes as both contributors to aging and tools for its modulation may open new avenues for interventions to promote healthy longevity.

Link: https://doi.org/10.1186/s12967-025-07379-1

Researchers here present indirect evidence for the toxic aggregation of amyloid-β and tau protein in the aging brain to drive the accumulation of white matter hyperintensities seen in brain imaging. These hyperintensities are areas of damage, resulting from a range of causes that include rupture of blood vessels, localized inflammatory response, and more. The more white matter damage in the brain, the worse the outcome in terms of cognitive loss and progression of neurodegenerative conditions.

White matter hyperintensities (WMHs) are increasingly recognized as markers of cerebrovascular pathology in Alzheimer's disease (AD), yet their temporal relationship with amyloid and tau accumulation remains unclear. While previous studies suggest bidirectional associations between WMHs and AD pathology, regional associations between WMHs and AD pathology have yet to be examined. This study investigated the temporal and regional associations between PET measures of amyloid (Aβ) and tau pathology and WMH burden in older adults.

Baseline analyses revealed significant bidirectional associations between WMH burden and both Aβ and tau pathology, with stronger effects in posterior brain regions. Longitudinal analyses showed that baseline Aβ levels were associated with future WMH progression in frontal and occipital regions, while baseline tau was linked to WMH increases in frontal and parietal regions. However, baseline WMH burden was not associated with future accumulation of either Aβ or tau pathology in any region. These findings suggest that Aβ and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.

Link: https://doi.org/10.64898/2025.12.18.25342588

Models are not reflections of real systems, but are better thought of as tools to help us understand how real systems might work under the hood. The production, assessment, and consideration of models over time helps researchers to constrain and guide research into real systems. Any individual model may not be all that helpful on its own. Certainly, its conclusions have to be considered in the context of the assumptions it makes and the behavior of different models in the same field.

Today's open access model discusses the Saturating-Removal model of aging, derived from observations of the growth in senescent cell burden with age and its contribution to degenerative aging. It is a form of damage accumulation model, perhaps more akin to reliability theory as applied to aging than other modeling in the field, though still quite different from that approach. The paper is an interesting read. As one might expect, the model of damage accumulation predicts that methods of damage repair - i.e. rejuvenation therapies that address issues such as senescent cell accumulation - will be needed to move the needle on human life span.

Maximal human lifespan in light of a mechanistic model of aging

There is a gap in understanding the rigidity of maximal human lifespan in terms of molecular and cellular mechanisms of aging. Despite advances in characterizing the molecular and cellular changes with age in humans and model organisms, it is unclear which mechanisms affect median and maximal lifespan differentially. For example, although it is often thought that aging is due to accumulating damage, it is not known how median and maximal lifespan are differentially affected by damage production rate, removal rate, stochastic noise, and threshold for death. Understanding which factors affect maximal lifespan may offer clues for future longevity interventions.

To address this, we applied an advance that links mechanistic aging processes to demographic variables such as median and maximal lifespan. This advance is a mathematical model of stochastic damage accumulation called the Saturating-Removal (SR) model (see chapter seven in Systems Medicine as a point of reference). The SR model was developed based on dynamics of senescent cells in mice and has since been shown to capture a wide range of aging patterns including the exponential rise in hazard with slowdown at old age, exponential disease incidence, effect of parabiosis, longevity interventions and their combinations, and aging differences between species. Recently, the model has been used to reexamine the heritability of human lifespan and provide insights into the compression of morbidity.

Here we show that variation in human lifespan is consistent with person-to-person differences in SR model parameters, subject to a strong constraint. Differences in damage production or removal rates greater than a few percent produce unrealistically long lifespans, whereas variation in threshold or noise preserves the observed upper limit near 120 years. This pattern is supported by analyses of NHANES exposure cohorts, centenarian sibling data, ages of the longest-lived individuals, and historical cohorts adjusted for extrinsic mortality. As a contrasting case, survival curves from Hutchinson-Gilford progeria - a disorder of accelerated aging due to nuclear lamina defects - indicate altered production dynamics.

Finally, we extended our analysis to additional mathematical models of aging and mortality and show that similar constraints apply. Together, these findings suggest that damage production and removal parameters in humans are tightly constrained with little person-to-person differences. Extending maximal human lifespan will require modifying the production or removal of aging-related damage, processes that appear largely unaffected by lifestyle, historical improvements, or common genetic variation.

Here find a tour of an aspect of mitochondrial structure that might be unfamiliar, the boundary between the inner and outer mitochondrial membranes and their features called the mitochondrial contact site and cristae organizing system (MICOS). It is of interest to the researchers here because their data shows that MICOS becomes particularly disarrayed in neurons exposed to Alzheimer's disease pathology, and mitochondrial dysfunction is a feature of Alzheimer's disease and aging more generally. Further research with a broader focus remains needed determine how this fits in to the present consensus on the age-related mitochondrial dysfunction that occurs throughout the body.

Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD.

Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.

Link: https://doi.org/10.64898/2025.12.13.693635

It is well established that greater physical fitness correlates with improved late life health and greater life expectancy. Here researchers report a modest decrease in the predicted age produced by a proteomic aging clock following a 12 week program of exercise. This is much as one would expect given what we know about the effects of regular exercise on long-term health, coupled to the point that most people in the wealthier regions of the world exercise too little and suffer the consequences in the form of faster age-related degeneration and a greater risk of age-related disease. Matters tend to improve when you take those people and have them undertake a greater amount of exercise.

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu, NCT01803568) in 26 men, ProtAgeGap decreased by the equivalent of 10 months.

While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk.

Link: https://doi.org/10.1038/s41514-025-00318-w