Fight 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.

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

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.

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.

Link: https://doi.org/10.64898/2025.12.16.694716

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.

Link: https://doi.org/10.1038/s41420-025-02913-y

That genetic variation appears to determine little of the variation in life expectancy for the vast majority of people is perhaps the most useful information yet to emerge from the creation of very large databases of genetic and health information, such as the UK Biobank. That this is the case doesn't rule out the existence of rare beneficial mutations with relatively large effects on life expectancy, however. See, for example, the PAI1 loss of function mutants who appear to live seven years longer than near relatives - though one should be wary of small sample sizes when it comes to determining the size of the effect in these circumstances.

In today's open access paper, researchers report on their identification of a rare mutation in cGAS, an important determinant of age-related chronic inflammation. When nuclear DNA or mitochondrial DNA is mislocalized in the cell as a result of age-related damage and dysfunction, cGAS is a part of the maladaptive process by which the STING pathway is triggered to produce an inflammatory response. This pathway evolved to defend against infectious pathogens, so one can't just turn off cGAS-STING signaling because it is essential to normal immune function and health. Too much of it is a bad thing, however, and important in degenerative aging. This newly discovered mutation appears to split the difference, resulting in greater longevity without evidently impaired function.

One might compare this discovery with recent work in the comparative biology of aging, where cGAS and STING are shown to be less inflammatory in response to the molecular damage of aging in long-lived species. For example, researchers have engineered mice to express the less inflammatory naked mole-rat cGAS, and this has the outcome of reducing age-related inflammation to slow degenerative aging. Similarly, another research group engineered mice to expresss the STING gene from bats, which also produced a beneficial reduction in age-related inflammation.

Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci.

Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.

Histones are structures in the cell nucleus that act as spools. Regions of nuclear DNA are compacted into a protected, inactive form when spooled around histones. The modification of histones by the addition and removal of chemical decorations are an important part of determining the winding and unwinding of DNA, and thus which gene sequences are exposed to translational machinery and can be expressed at any given time. One sizable component of aging is that this highly complex regulation of DNA structure changes, altering gene expression in undesirable ways.

Researchers here take initial steps towards mapping the effects on aging of succinylation of histones, the addition of a succinyl group. Their initial data suggests that more succinylation is a good thing, in that it correlates with greater longevity and a slower pace of aging. Providing mice with a diet supplemented with succinic acid to provoke greater histone succinylation produces modest benefits. That more succinylation is beneficial in this way is an unexpectedly direct outcome for something as complex as regulation of histone function, but the data is the data.

Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood.

Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization.

To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.

Link: https://doi.org/10.1111/acel.70346

Researchers here discuss the application of lipid nanoparticle delivery of messenger RNA as a basis for the development of cancer vaccines. As is the case for vaccines against infectious disease, there are many different ways to provoke an immune response to cancer-specific antigens. Use of messenger RNA to express the desired antigen is the most recent of these technologies. A great of effort has gone into the development of cancer vaccines over the years, and thus it seems likely that a wide range of messenger RNA cancer vaccines will be developed. As yet, however, little of this past effort has resulted in regulatory approval of cancer vaccines and use in the clinic. That low success rate may or may not change with the introduction of messenger RNA as an approach, time will tell.

The landscape of cancer immunotherapy has been redefined by mRNA vaccines as rapid clinically viable strategies that help induce potent, tumor-specific immune responses. This review highlights the current advances in mRNA engineering and antigen design to establish an integrated immunological framework for cancer vaccine development.

Achieving durable clinical benefit requires more than antigen expression. Effective vaccines need precise epitope selection, optimized delivery systems, and rigorous immune monitoring. The field is shifting from merely inducing immune responses to focusing more on the biochemistry and molecular design principles that combine magnitude, polyfunctionality, and longevity to overcome tumor-induced immune suppression.

We examine an integrated immunological framework for mRNA cancer vaccine development, examining how rational molecular engineering of vaccine components, from nucleoside modifications and codon optimization to untranslated regions and linker sequences, shapes immunogenicity and therapeutic efficacy. Future directions will depend on balancing combinatorial strategies combining vaccination with immune checkpoint inhibitors and adoptive cell therapies.

Link: https://doi.org/10.3390/vaccines13121222

The proof of concept demonstration outlined in today's research materials is chiefly interesting as a demonstration that energy metabolism may be more important than suspected in the onset and progression of Alzheimer's disease. The brain has high energy requirements, and it was certainly thought that age-related neurodegeneration is caused in part by the negative impact on energy metabolism of a reduced supply of oxygen and nutrients to the brain alongside impaired mitochondrial function. But how big is that part, relative to other contributions? This is always the question, and the fastest way to obtain answers remains to try various forms of therapy and observe the results.

The cautions here are twofold. Firstly that Alzheimer's mouse models are artificial and each model encapsulates assumptions about the driving pathology of the condition that may or may not be relevant in humans. Mouse model Alzheimer's pathology is not the human disease. Secondly, the researchers here focus on NAD+, a necessary component of mitochondrial energy metabolism that declines in availability with age. While they claim important differences in the specifics of the approach taken, increasing NAD+ levels via vitamin B3 derivatives and a few other methodologies has in the past performed poorly in clinical trials for a range of conditions. So on the one hand the data in mice presented here is quite good, and may indeed say something important about energy metabolism in the aging brain, but on the other both the approach taken and the models used come with caveats.

New Study Shows Alzheimer's Disease Can Be Reversed in Animal Models to Achieve Full Neurological Recovery, Not Just Prevented or Slowed

Researchers have shown that the brain's failure to maintain normal levels of a central cellular energy molecule, NAD+, is a major driver of Alzheimer's disease (AD), and that maintaining proper NAD+ balance can prevent and even reverse the disease. NAD+ levels decline naturally across the body, including the brain, as people age. Without proper NAD+ balance, cells eventually become unable to execute critical processes required for proper functioning and survival. In this study, the team showed that the decline in NAD+ is even more severe in the brains of people with AD, and that this also occurs in mouse models of the disease.

After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing the loss of brain NAD+ balance before disease onset, or restoring brain NAD+ balance after significant disease progression, could prevent or reverse AD, respectively, using a well-characterized pharmacologic agent known as P7C3-A20.

Not only did preserving NAD+ balance protect mice from developing AD, but delayed treatment in mice with advanced disease also enabled the brain to fix the major pathological events of AD. Moreover, both lines of mice fully recovered cognitive function. This was accompanied by normalized blood levels of phosphorylated tau 217, a recently approved clinical biomarker of AD in people, providing confirmation of disease reversal and highlighting a potential biomarker for future clinical trials.

Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain

Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD+) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217.

P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD+ homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD+ homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.

Companies working on novel therapeutics targeting senescent cells, to selectively destroy these errant cells or alter their metabolism to reduce harmful inflammatory signaling, are largely steering clear of neurodegenerative conditions, at least for now. Any successful systemic treatment that destroys senescent cells or suppresses the inflammatory signaling of senescent cells throughout the body will likely see off-label use for many age-related conditions, of course, but not all such treatments will affect the burden of senescent cells in the brain. The present consensus in the research community is that cellular senescence in the various populations of supporting cells in the brain appears to be important in the onset and development of neurodegenerative conditions, and therefore more attention should be given to the application of senotherapeutics to the aging of the brain.

Cellular senescence is a state of stable cell cycle arrest, initially identified in proliferative cells, accompanied by persistent metabolic activity and the secretion of a pro-inflammatory cocktail of molecules known as the senescence-associated secretory phenotype (SASP). Initially, it acts as a beneficial mechanism by halting the proliferation of damaged cells, thus suppressing tumor development, and facilitating wound repair through the coordinated release of specific factors. The pathology arises from the chronic accumulation of these senescent cells. Their persistent SASP creates a toxic tissue environment. In the brain, the accumulation of senescent microglia and astrocytes is a major driver of neuroinflammation. Recent studies directly link this process to cognitive decline and neurodegenerative pathologies, making the clearance of senescent cells (senolysis) a promising strategy to combat brain aging.

The identification of senescence as a modifiable factor in brain aging has led to the emergence of senotherapeutics, a new class of pharmacological interventions aimed at either eliminating senescent cells (senolytics) or modulating their harmful secretory profile (senomorphics). Senolytics, such as dasatinib and quercetin, selectively induce apoptosis in senescent cells by targeting pro-survival pathways unique to the senescent state.

Senotherapeutics offer a promising and innovative approach to managing brain aging and its associated cognitive decline. By targeting the fundamental process of cellular senescence, either through selective elimination of senescent cells or modulation of their harmful secretions, these interventions have demonstrated the ability to reduce neuroinflammation, improve synaptic function, and enhance cognitive performance in preclinical models. Although clinical translation is still in early stages, ongoing trials and emerging delivery technologies provide a pathway toward safe and effective use in humans. Challenges such as blood-brain barrier permeability, senescence biomarker development, and long-term safety must be addressed through continued research and technological advancement.

Link: https://doi.org/10.3390/neurolint17120204

The lack of consistency between clinical trials conducted for any given medical condition is a continual point of complaint in the research community. It is a hard problem to solve, as illustrated by the long history of such complaints and little consequent difference in the state of trial design. Still, one can make efforts. The best way forward is perhaps to propose a detailed standard and then advocate for it. For the longevity field, the authors of this paper take a first step in that direction with a set of recommendations for data collection in studies of therapies to treat aging.

Biomarkers of aging have the potential to transform geroscience clinical trials because of their broad applications in stratifying participants, prioritizing interventions, and monitoring responses to geroprotectors. As longevity biotechnology companies (LBCs) continue to plan and launch innovative clinical trials, standard practices in collecting data and applying biomarkers of aging will allow the field to support parallel and ongoing validation and benchmarking efforts for aging biomarkers. Moreover, defining standard best practices will ensure future reuse of valuable clinical data. Here, we propose recommendations for such collections. We believe that wide adoption of these recommendations will allow LBCs to produce and leverage the highest quality data from their clinical trials, while also benefiting the geroscience field more broadly with minimal additional effort.

In an ideal world, studies would collect as many samples as possible in order to establish a repository of biospecimens and data for research. Although a comprehensive repository is useful, it may not be feasible for collection in all trial protocols. As such, we propose a prioritization framework for assessment of what is most important to collect, based on three main pillars: 1) feasibility, 2) representation, and 3) range of use. Feasibility refers to the effort required for collection in trials; representation refers to how representative the sample is of the overall aging process; and range of use relates to the number of different analyses that can be conducted with the sample. Based on these criteria, we recommend that, at minimum, blood, which provides a snapshot of biological features, and wearable data, providing continuous information on functional features, should be collected and stored.

In addition to the importance of collecting biological and wearable data, it is essential to collect corresponding participant information. Associated data should include detailed demographic information, medical history, family medical history, and health outcome data, where possible. Irrespective of the indication under assessment in the trial, a broad range of health outcomes corresponding to age-related disease (e.g. cardiovascular diseases, dementia, and cancers) should be monitored, with monitored outcomes determined by balancing additional trial complexity and data richness, and also considering the length of the study.

Informed patient consent is an essential part of all clinical trial protocols, ensuring the subjects understand the purpose of a trial, what data will be collected and processed, and their responsibilities and rights as a study participant, including the ability to cease participation at any time. Beyond the minimum consent requirements for clinical trials, it is becoming increasingly important to obtain explicit consent for future activities associated with biomarker research and analysis of biobanked samples to reduce the need to re-engage trial participants for consent once the trial has been completed.

Link: https://doi.org/10.1038/s41514-025-00313-1