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- Restoration of Lymphatic Vessel Contractility in Aged Mice
- The Saturating-Removal Model of Damage Accumulation and Effects of Lifestyle on Aging
- A Small Sample of the Complexity of Hair Follicle Aging
- In Search of Mechanisms to Explain the Sex Difference in Alzheimer's Disease Outcomes
- Dementia Risk Varies Between Strong versus Weak Circadian Clock Regulation
- Targeting Mitophagy to Slow Aging
- Senescent T Cells Accumulate with Age, Impairing Immune Function
- Modest Reversal of Proteomic Aging via a Structured Program of Exercise
- MICOS in the Age-Related Decline of Mitochondrial Function
- Evidence for Tau and Amyloid Pathology to Drive White Matter Damage in the Brain
- Exosomes in Aging and Age-Related Conditions
- Improved Drainage of Cerebrospinal Fluid as a Time Critical Treatment for Stroke
- Reduced Cystathionine γ-lyase Levels May Contribute Meaningfully to Age-Related Neurodegeneration
- Retro Biosciences Starts a Safety Trial for an Autophagy Promoter
- Physical Activity Reduces Epigenetic Age and Inflammatory Signaling
Restoration of Lymphatic Vessel Contractility in Aged Mice
https://www.fightaging.org/archives/2026/01/restoration-of-lymphatic-vessel-contractility-in-aged-mice/
At the high level, the lymphatic system has a lot in common with the vascular system. The cargo is lymph and immune cells rather than blood and immune cells, but the structure and function of vessels is quite similar. Both types of vessel are lined with endothelial cells, while a layer of smooth muscle manages contraction, dilation, and pulsation of vessels to manage volume, pressure, and fluid flow. Like blood vessels, lymphatic vessels exhibit dysfunction with age, such as in their ability to appropriately contract and dilate. This impairs fluid flow, producing a range of consequences. One of the more recently discovered issues is the impaired drainage of cerebrospinal fluid from the brain via the glymphatic system, a potentially important contribution to neurodegenerative conditions. There are others.
A great deal of effort has gone into developing drugs that influence the biochemistry regulating the action of smooth muscle in blood vessels, as this is one of the ways to force a reduction in high blood pressure. Now that researchers have compelling reasons to turn their focus towards analogous issues in the lymphatic system, there is a vast body of work to pull from, and many existing drugs and drug candidates to assess in animal studies. Interestingly, in today's open access paper, researchers report considerable success in restoring the contractility of lymphatic vessels in aged mice by exploiting a mechanism that doesn't occur in blood vessels. The results suggest that the specific approach taken should be developed and tested as a way to slow the onset of neurodegenerative conditions by restoring drainage of cerebrospinal fluid.
Selective Activation of NaV1.3 Restores Lymphatic Contractility in Age and Injury
Intrinsic lymphatic contractility is essential for tissue fluid balance, immunity, and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3 (also known as SCN3A), a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain.
In mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with the NaV1.3-specific activator Tf2 (derived from scorpion venom) increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in NaV1.3 knockout mice, confirming NaV1.3 dependence.
In conclusion, NaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.
The Saturating-Removal Model of Damage Accumulation and Effects of Lifestyle on Aging
https://www.fightaging.org/archives/2026/01/the-saturating-removal-model-of-damage-accumulation-and-effects-of-lifestyle-on-aging/
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.
A Small Sample of the Complexity of Hair Follicle Aging
https://www.fightaging.org/archives/2026/01/a-small-sample-of-the-complexity-of-hair-follicle-aging/
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.
In Search of Mechanisms to Explain the Sex Difference in Alzheimer's Disease Outcomes
https://www.fightaging.org/archives/2026/01/in-search-of-mechanisms-to-explain-the-sex-difference-in-alzheimers-disease-outcomes/
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.
Dementia Risk Varies Between Strong versus Weak Circadian Clock Regulation
https://www.fightaging.org/archives/2026/01/dementia-risk-varies-between-strong-versus-weak-circadian-clock-regulation/
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.
Targeting Mitophagy to Slow Aging
https://www.fightaging.org/archives/2026/01/targeting-mitophagy-to-slow-aging/
Autophagy is the name given to an important collection of processes that identify broken and unwanted cellular structures and convey them to a lysosome, where they are broken down and recycled. The identification and conveyance differ greatly from target to target, but all of the specific forms of autophagy converge on delivery to a lysosome. Up to a point, more autophagy and more efficient autophagy improves cell function by clearing out damaged and dysfunctional structures and protein machinery. This in turn translates to a modest slowing of aging if sustained over time throughout the body, which is why the research community spends so much time focused on autophagy. Here, researchers discuss mitophagy, meaning autophagy of mitochondria, and its importance in maintaining cell function.
Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1).
During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.
Senescent T Cells Accumulate with Age, Impairing Immune Function
https://www.fightaging.org/archives/2026/01/senescent-t-cells-accumulate-with-age-impairing-immune-function/
Senescent cells accumulate with age as the immune system slows down and clears them less effectively. The immune system itself also accumulates senescent cells of various types. Once senescent, a cell ceases to replicate, grows in size, and generates pro-growth, pro-inflammatory signaling that becomes harmful when sustained over time. The more senescent cells in the body, the worse the outcome of this signaling; senescent cells are an important component of degenerative aging. Here, researchers focus on effector T cells, important to the immune response, and which become senescent in increasing numbers with age.
Senescent cells play important roles in various biological processes that promote fitness and health, however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells progressively accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. Supporting this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans.
Here, we further characterized the senescence state of human SA-βGal-expressing CD8 T effector cells, their functional capabilities, and their involvement in aging and disease. Single-cell RNA sequencing revealed that SA-βGal-expressing CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in effector memory (em) T cells.
SA-βGal-expressing CD8 Tem cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells, compared to CD8 Tem cells with low SA-βGal activity. Gene signatures of senescent SA-βGal-expressing CD8 Tem cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and smokers. Furthermore, our results demonstrate that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 Tem cells to immunotherapy.
Modest Reversal of Proteomic Aging via a Structured Program of Exercise
https://www.fightaging.org/archives/2026/01/modest-reversal-of-proteomic-aging-via-a-structured-program-of-exercise/
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.
MICOS in the Age-Related Decline of Mitochondrial Function
https://www.fightaging.org/archives/2026/01/micos-in-the-age-related-decline-of-mitochondrial-function/
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.
Evidence for Tau and Amyloid Pathology to Drive White Matter Damage in the Brain
https://www.fightaging.org/archives/2026/01/evidence-for-tau-and-amyloid-pathology-to-drive-white-matter-damage-in-the-brain/
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.
Exosomes in Aging and Age-Related Conditions
https://www.fightaging.org/archives/2026/01/exosomes-in-aging-and-age-related-conditions/
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.
Improved Drainage of Cerebrospinal Fluid as a Time Critical Treatment for Stroke
https://www.fightaging.org/archives/2026/01/improved-drainage-of-cerebrospinal-fluid-as-a-time-critical-treatment-for-stroke/
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."
Reduced Cystathionine γ-lyase Levels May Contribute Meaningfully to Age-Related Neurodegeneration
https://www.fightaging.org/archives/2026/01/reduced-cystathionine-%ce%b3-lyase-levels-may-contribute-meaningfully-to-age-related-neurodegeneration/
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.
Retro Biosciences Starts a Safety Trial for an Autophagy Promoter
https://www.fightaging.org/archives/2026/01/retro-biosciences-starts-a-safety-trial-for-an-autophagy-promoter/
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.
Physical Activity Reduces Epigenetic Age and Inflammatory Signaling
https://www.fightaging.org/archives/2026/01/physical-activity-reduces-epigenetic-age-and-inflammatory-signaling/
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.
View the full article at FightAging
