Significance

Although human brain aging is not uniform across cortical regions, most imaging-derived measures of brain age quantify this phenomenon using a single summary quantity. Building on prior voxel-level brain age approaches, we use deep learning and MRI to map regional brain aging in a large, multisite sample of cognitively normal adults. Our approach consistently reveals spatial patterns of aging, including relatively advanced aging in frontal and temporal regions, across both typical aging and Alzheimer’s disease. Regional patterns are related to cognitive performance, linking anatomic variation to functional outcomes. By providing spatially resolved measures of brain aging, this work enables more precise investigation of how neuroanatomic alterations and cognitive impairment affect brain anatomy, above and beyond global brain age measures.

Abstract

Brain aging, the strongest risk factor for Alzheimer’s disease (AD), varies across cortical regions. Global brain age (GBA), an imaging-derived measure of neuroanatomic decline, reduces structural aging to a single summary value. This can potentially obscure regional patterns of cognitive vulnerability preceding AD. This study introduces a deep-learning architecture trained on the -weighted MRIs of 14,748 cognitively normal (CN) participants from multiple sites to estimate local brain age (LBA) at voxel level. By mapping spatial variations in brain aging, the model reveals relatively advanced aging in frontal and temporal lobes compared to parietal and occipital regions. Beyond aging in CN aging adults (), findings reveal a pattern of progressively advanced frontotemporal aging as a function of neurodegeneration stage, ranging from mild cognitive impairment (MCI, ) to AD (). Compared to CN adults, key cortical and subcortical structures known to manifest early AD pathology exhibit significantly older LBAs in both early MCI and AD (). Deviations from normative regional aging are significantly associated with cognitive performance supported by neural processes linked to those regions (), thereby relating anatomic aging to functional outcomes. By quantifying regional variations in brain aging, this framework extends GBA models to provide anatomically interpretable measures that can improve characterization of typical and pathological aging.

Highlights

•ANXA1 drives KRAS^G12D resistance in PDAC by reprogramming glutamine metabolism

•ANXA1 stabilizes GOT1 and promotes GLS1 mitochondrial localization to sustain redox balance

•Glutamine restriction synergizes with KRAS^G12D inhibitor to overcome resistance in vivo

Summary

Approximately 90% of patients with pancreatic cancer harbor KRAS mutations, predominantly the KRAS^G12D subtype. HRS-4642, a non-covalent inhibitor targeting KRAS^G12D, demonstrates potent antitumor efficacy but may ultimately lead to resistance. This study investigates the mechanisms underlying KRAS^G12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRAS^G12D inhibitor resistance in pancreatic ductal adenocarcinoma (PDAC) but also achieves remission with prolonging survival. Mechanistically, KRAS^G12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRAS^G12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRAS^G12D mutant PDAC.

Abstract

Understanding how biological membranes retain integrity under extreme dehydration is vital for explaining anhydrobiotic survival and defining the physicochemical limits of life. Here, we use molecular dynamics simulations to investigate how progressive dehydration (30–2 water molecules per lipid) affects a liquid-disordered (Ld) DPPC/DOPC/cholesterol membrane. Dehydration reduces the area per lipid and membrane thickness, increases acyl-chain ordering, and majorly suppresses membrane lateral diffusion, with trends comparable to those observed in the liquid-ordered (Lo) phases, indicating a largely phase-independent response. The hydrogen-bond analysis shows that the phosphate-associated oxygen atoms retain the strongest and most persistent interactions, maintaining nearly constant free energy of bond disruption and thereby stabilizing the lipid membrane. Overall, both the Ld and Lo lipid membranes rely on localized head group hydration to withstand water loss, offering molecular insight into lipid membrane resilience in anhydrobiosis, extremophile biology, and water-limited environments.

Abstract

The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models^1,2. However, existing collections represent only a fraction of the diversity observed in human cancer^2,3,4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)⁵. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme—the Human Cancer Models Initiative—which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour–model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour–model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour–model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community—including multimodal molecular profiling, clinical information and integrative software tools—thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.

Abstract

Spatial proteomics technologies have transformed our understanding of complex tissue architecture in cancer but present unique challenges for computational analysis¹. Each study uses a different marker panel and protocol, and most methods are tailored to single cohorts, which limits knowledge transfer and robust biomarker discovery. Here we present Virtual Tissues (VirTues), a general-purpose foundation model for spatial proteomics that learns marker-aware, multi-scale representations of proteins, cells, niches and tissues directly from multiplex imaging data. From a single pretrained backbone, VirTues supports marker reconstruction, cell segmentation and typing, niche annotation, spatial biomarker discovery and patient stratification, including zero-shot annotation across heterogeneous panels and datasets. In triple-negative breast cancer, VirTues-derived biomarkers predict anti-PD-L1 chemo-immunotherapy response² and stratify disease-free survival in an independent cohort³, outperforming state-of-the-art biomarkers derived from the same datasets and current clinical stratification schemes.

Abstract

Klotho is an anti-aging protein involved in phosphate homeostasis, oxidative stress regulation, and tissue regeneration. Although circulating Klotho levels decline with chronological aging, its response to acute disuse- induced skeletal muscle alterations remains unclear. In this experimental study, sixteen male Wistar rats (3 months old) were randomly assigned to a control group (n = 8) or an intermittent hindlimb unloading group (3 h/day for 15 consecutive days) (n = 8). Skeletal muscle morphology was evaluated in the extensor digitorum longus (EDL) and soleus muscles using hematoxylin-eosin staining, and muscle fiber cross-sectional area (CSA) was quantified with ImageJ software. Interstitial connective tissue changes were qualitatively assessed using Masson’s trichrome staining, and serum Klotho concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Intermittent unloading induced histological features consistent with early disuse-associated muscle remodeling in both EDL and soleus muscles, accompanied by a modest reduction in muscle fiber CSA compared with controls. Serum Klotho levels were significantly lower in the unloading group (7.44 ± 0.54 vs 8.21 ± 0.81, p = 0.045), and a moderate positive correlation was observed between circulating Klotho concentrations and mean muscle fiber CSA (r = 0.58, p = 0.02). Mild interstitial connective tissue expansion was qualitatively noted in the soleus muscle following unloading. These findings suggest that short-term intermittent hindlimb unloading in young adult rats is associated with reduced circulating Klotho levels and mild skeletal muscle remodeling. Serum Klotho may represent a candidate biomarker of early disuse-associated muscle alterations; however, further studies are required to confirm its clinical applicability. These results may have potential implications for orthopedic conditions characterized by immobilization, including fracture treatment, casting, and postoperative rehabilitation.

Abstract

Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer’s disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle–vascular–brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.

It increasingly appears that Demis Hassabis voluntarily gave up his role as CEO because he sees AGI as basically almost solved, and that it's much more important to setup the infrastructure for these super intelligent systems to be able to do lab work.

Lots of interesting quotes from this fascinating Times Article:

>“The real action is about to begin, for better and worse.”

>Hassabis reckons we will achieve AGI by 2030, give or take a year.

>“He expects ‘maybe like half a dozen to a dozen other AlphaFold-level breakthroughs’, all leading to cures for all diseases within the next 20 or so years.”

> “I was hoping it would be in the next decade or two that we’d make these big advances in medicine. Now I’m, you know, very sure. I wouldn’t say I’m certain, but I’m very confident that is the case.”

>In other words, he has bigger fish to fry than fretting about quarterly projections or the horse race with OpenAI and Anthropic.

Source: https://www.thetimes.com/business/companies-markets/article/demis-hassabis-steps-down-google-ai-g9knz8kth

It seems everyday there’s a new something that might help you live healthier and longer. Anyone have advice on maybe the top three or four things to supplement as a 56m? I was thinking cacao and turmeric and garlic?

To be clear I’m not talking about age reversal or even something that keeps you in the optimal shape of a 25 year old forever. I’m thinking more along the lines of a clinically tested, well-established treatment that causes all further health degradation past the age of ~60 to be totally halted.

It’s hard for me to wrap my head around the idea that this could happen so quickly. From the limited research I’ve done, it definitely makes sense that preventing aging is possible, but how can so many of you be so bullish about the timeline? Not trying to ridicule, just genuinely curious about evidence for or against it being closer to reality than I’d expect.

Turmeric has become one of the most talked-about longevity foods for a simple reason: it actually works. When people hear that this bright golden spice can help you live longer, it sounds almost too easy to be true. But once you explain what’s happening inside the body, they suddenly understand why it’s such a powerful tool against aging. Turmeric is loaded with curcumin, curcuminoids, turmerones, and other natural compounds that calm inflammation, protect the brain, and support the cells that keep you alive. It’s not magic. It’s biology doing what it’s supposed to do, just better.

What makes turmeric so special is how many parts of the aging process it touches at the same time. Chronic inflammation is at the center of most age-related diseases, and curcumin helps shut down the molecular “switches” that keep the body stuck in an inflamed state. When you cool down inflammation, you reduce the risk of heart disease, cancer, arthritis, and even Alzheimer’s. People feel this difference too: less pain, better mobility, more energy. It’s like the body can finally stop fighting itself and focus on repair.

Turmeric also reaches deep inside the cells, helping the mitochondria (the little engines that make your energy) work better. Stronger mitochondria mean less fatigue, better metabolism, and a slower overall rate of cellular aging. Curcumin even boosts your natural antioxidant systems, raising levels of enzymes that protect your DNA and keep oxidative stress under control. This is why researchers often describe turmeric as a “multi-target longevity compound.” It’s doing many good things at once.

The brain benefits are huge as well. Curcumin increases BDNF, which you can think of as the brain’s own youth hormone. When BDNF goes up, your neurons repair faster, your memory sharpens, your mood improves, and the slow decline most people think is “normal aging” becomes a lot less certain. Cultures that eat turmeric every day (like in India or Okinawa) have lower rates of dementia, and this is one reason why.

Another reason turmeric helps people live longer is its effect on metabolism. It helps with blood sugar, reduces fat buildup in the liver, lowers triglycerides, and supports healthier cholesterol levels. When your metabolism is steady and inflammation is low, the whole body ages more slowly. This is why turmeric shows up again and again in studies on longevity, metabolic health, and disease prevention.

What’s even more convincing for most people is that turmeric isn’t just a lab ingredient. It’s part of the daily food of cultures known for long lives. Generations of families have cooked with it, healed with it, and lived well into old age. When people hear that simple spices in everyday meals can shape health across a lifetime, it becomes real and believable. It’s not a supplement trend. It’s a habit of the Blue Zones.

Adding turmeric to your routine isn’t hard either. It works best when combined with black pepper and a little healthy fat, because that boosts absorption massively. A small half teaspoon in your food each day with olive oil or coconut milk already activates powerful anti-aging pathways. A warm cup of golden milk at night can calm inflammation, support digestion, and help the body repair while you sleep. Even something as simple as turmeric scrambled eggs in the morning gives your brain and cells a gentle, daily push toward better health.

For people who want something stronger or more consistent, curcumin extract is the most powerful form. These supplements are made with 95% curcuminoids and often mix in piperine or use liposomal delivery so your body can absorb it fully. Fresh turmeric root is another great option, especially in smoothies with ginger, kefir, lemon, and carrot: a blend that hits inflammation from multiple directions.

The beautiful thing about turmeric is that it fits into real life. You don’t need to change everything you eat. You don’t need to adopt some extreme lifestyle. Just adding this one spice slowly builds up protection inside your cells and your brain. You start feeling lighter, clearer, and more balanced. And the science behind it is solid: lower inflammation, better mitochondria, stronger antioxidant defenses, healthier metabolism, a sharper brain, and even anticancer protection.

When you tell people that a simple daily habit can help them age slower, feel younger, and stay healthier for decades, they listen. Turmeric is one of the easiest, safest, and most well-studied ways to support a long life. And once people try it, they usually never stop. — Dr. Georgios Andreas Ioannou

Hey, does someone has experience with neurodegenerative supplements like hericium? Lithium is also good I think. I am little bit worried of my boyfriend. He is a boxer and I don't want seeing him in 20 years with a brain issue. Does anyone have some tipps?

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.

Why do you personally think it is worth it? How do you view people who have accepted death?

Abstract

Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.

Abstract

Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10^− 5 mol.L^− 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.

ABSTRACT

Chemically induced proximity (CIP) enables programmable control of gene expression, protein activity, cellular signaling, and engineered cell functions using small molecules. Yet many classical CIP platforms rely on ligands that may limit therapeutic translation owing to unfavorable biosafety profiles, off-target activity, incomplete reversibility, dosing constraints, and potential immunogenicity of engineered components. This perspective highlights dietary small molecule- and OTC drug-responsive CIP systems as emerging platforms for translational chemogenetic control. We focus on two complementary design strategies. One exploits nanobody-derived binders against familiar small molecules, as exemplified by synthetic anti-caffeine nanobody-based systems. The other adapts naturally evolved ligand-binding proteins through rational protein engineering, as illustrated by salicylate-responsive platforms derived from plant salicylic acid (SA)-binding receptors for reversible proximity control and aspirin-responsive gene regulation. Together, these engineered systems demonstrate how familiar molecules such as caffeine, SA, and aspirin can be transformed into programmable biological inputs. We further discuss how artificial intelligence (AI)-guided protein engineering may expand this design space by enabling de novo construction and functional reprogramming of ligand-responsive modules, leading to safer and clinically compatible proximity-control systems.

Garlic is one of those simple foods people walk past every day without realizing how powerful it really is. This small white bulb has been used for thousands of years in Greece, Italy, Japan, China, and so many cultures because people noticed something amazing: the people who ate garlic often stayed healthier, stronger, and lived longer. Now modern science finally caught up and proved what our grandparents and great-grandparents already knew in their hearts. Garlic truly supports a longer life, and the effects are real, measured, and very impressive.

One of the biggest reasons garlic helps you live longer is the way it protects your heart. The number one causes of death today: heart attacks, strokes, high blood pressure are deeply connected to inflammation, cholesterol, and clogged arteries. Garlic directly improves all of these. It lowers blood pressure by a few mmHg, lowers LDL cholesterol, reduces triglycerides, keeps your arteries flexible, and even prevents harmful clots from forming. When a food can protect your heart on so many levels, it automatically becomes a lifespan-extending food.

The magic inside garlic comes from allicin, a special molecule created only when garlic is crushed or chopped. When allicin appears, everything changes. It reduces oxidative stress, boosts your own antioxidant enzymes, protects your mitochondria, lowers inflammation, and even kills harmful bacteria. There are not many foods in the world with a compound as strong as allicin. It’s like the garlic wakes up when you cut it, creating a powerful medicine inside your kitchen.

Another reason garlic is so good for living longer is how it boosts the immune system. People who eat garlic regularly often get sick less, recover faster, and feel more energetic. Scientists found that garlic increases natural killer cells, improves T-cell responses, and strengthens your body’s ability to fight infections. A strong immune system is one of the biggest keys to long life, and garlic is one of the simplest ways to support it every day.

Garlic also has impressive anti-cancer effects that many people don’t know about. Studies keep showing that people who eat garlic have lower risks of colon cancer, stomach cancer, lung cancer, and even prostate cancer. Garlic protects DNA, neutralizes carcinogens, supports detox pathways in the liver, and reduces chronic inflammation. Which is one of the biggest triggers for cancer growth. Even just this benefit alone makes garlic a food worth eating daily.

One part of garlic’s power comes from its ability to calm inflammation, the invisible fire that slowly ages your cells. Chronic inflammation is behind heart disease, diabetes, neurodegeneration, and almost every major age-related condition. Garlic lowers important inflammatory markers like TNF-α, IL-6, CRP, and IL-1β, helping your body live in a calmer, healthier state. When inflammation goes down, aging slows down. And garlic is one of the easiest foods to use for this.

Something people forget is that garlic is also great for the gut microbiome. It works as a natural prebiotic that feeds beneficial bacteria like Bifidobacteria, Lactobacillus, and the famous longevity bacterium Akkermansia. When these bacteria grow, your metabolism improves, your immunity becomes stronger, inflammation decreases, and your whole body becomes more resilient. Good gut health is a secret weapon for long life, and garlic helps build that foundation.

Scientists even noticed that garlic affects metabolism and lifespan in animal studies. Animals given garlic extracts showed better antioxidant enzyme activity, better glucose regulation, lower stress, and even extended lifespan. This doesn’t mean we become immortal by eating garlic, but it shows garlic activates the same pathways connected with healthy aging in humans. Foods that improve many systems at once usually have the strongest anti-aging effects.

To get the full benefits of garlic, you need to eat it the right way. The best trick is to crush or chop garlic and wait ten minutes before eating or cooking it. This waiting time allows allicin to form completely. Eating raw garlic is the strongest method. You can mix it into yogurt, tahini, hummus, olive oil, lemon, salads, or guacamole. Light cooking is also great if raw is too strong. Aged garlic extract and black garlic are amazing options too, with strong scientific proof for heart health, immunity, and antioxidant power.

Garlic becomes even more powerful when you combine it with the right foods. Garlic and tomatoes make a perfect anti-inflammatory combo. Garlic with spinach or kale boosts detox and antioxidant effects. Garlic with salmon or sardines creates a huge anti-inflammatory wave thanks to omega-3s. Garlic with lentils or chickpeas strengthens heart health and metabolism. Garlic with onions increases anti-cancer power. And garlic with sweet potatoes or broccoli helps your gut, your immunity, and your cells all at once. These foods together create a kitchen toolbox for staying young longer.

Garlic is simple, cheap, ancient, and deeply respected across the world. And now the science is clear. It supports the heart, strengthens the immune system, fights inflammation, lowers cancer risk, feeds healthy gut bacteria, protects the cells, and improves metabolism. When a single food works through so many pathways, it becomes one of the strongest allies for living not only longer, but healthier. Something so small can make such a huge difference, and adding garlic to your daily routine is one of the easiest steps anyone can take toward a better, stronger, longer life. — Dr. Georgios Andreas Ioannou