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Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key...

Neuromodulation aims to improve brain function by altering neural activity. While many rehabilitation strategies seek to restore normal, healthy-like dynamics, some adopt a complementary strategy, using neuromodulation to strengthen repurposed processes that support function. Here we formalize these approaches as 'restorative normalization' (RN) and 'compensatory amplification' (CA), respectively. Drawing on cognitive neurophysiology, we evaluate the following four factors that enable CA to be...

Androgenetic alopecia (AGA) is the most common form of non-scarring hair loss, driven by genetic factors and increased sensitivity of scalp hair follicles to dihydrotestosterone (DHT), which causes progressive miniaturization of dermal papilla cells and shortens the hair growth phase. The precise molecular pathogenesis of AGA remains incompletely understood. The study aimed to elucidate the regulatory mechanism between secreted frizzled-related protein 2 (SFRP2) and follistatin-like 1 (FSTL1),...

Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model. Midlife Ghr...

NIH director defends interagency plan as “100% aligned with our public health mission”

A substance found in edible sea squirts appeared to reverse several signs of aging in older mice. Plasmalogen supplements improved memory and learning, strengthened connections between brain cells, reduced inflammation, and even helped the mice grow thicker, darker hair. Researchers believe the compounds may encourage brain regeneration and protect aging synapses.

Slow breathing with a prolonged exhale made people more willing to take risks by changing heart activity and increasing the brain’s sensitivity to rewards. The findings suggest that something as simple as controlling your breath can directly influence how you evaluate choices.

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Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression,...

The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling...

Both serum serotonin and cardiovascular-risk (CVR) burden are implicated in Alzheimer's disease (AD)-related vascular and neurodegenerative processes, yet their interrelationship across the AD continuum remains unclear. This cross-sectional study examined whether serum serotonin was associated with three complementary measures of CVR burden across the AD continuum and according to CSF amyloid status in 428 participants (138 cognitively normal [CN] individuals, 206 participants with mild...

Precise regulation of organ size is essential for proper function, yet the underlying logic remains unclear. Here, we identify a Hippo-IGF2 signaling axis as a regulator of organ growth. During mouse liver development, Igf2 is highly expressed in fetal and neonatal hepatocytes to fuel rapid growth but is directly silenced by the Hippo signaling pathway at the postnatal stage, enforcing growth arrest and determining liver size. In contrast, chronic liver injury inactivates Hippo signaling and...

As the body's primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual Protein homeostasis (proteostasis) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression,...

The global aging trend underscores the urgent need for innovative interventions against aging-related decline. Accumulating evidence identifies Akkermansia muciniphila (A. muciniphila) as a key gut microbiota regulator of aging, with its depletion associated with age-related diseases (ARDs), whereas its abundance is enriched in healthy centenarians. This review summarized current evidence linking A. muciniphila to aging, examining their causal relationship, the roles of its bioactive...

Although aging and cancer share complex molecular mechanisms, distinguishing causative factors from byproducts remains challenging. Here, we investigated the role of tissue transcriptomic entropy-a measure of transcriptional disorder-in aging and cancer processes by analyzing RNA-sequencing data from over 25,000 samples from human and mouse tissues. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or...

Protein posttranslational modifications (PTMs) play a central role for regulating protein function and cellular processes, with many PTMs arising from reactions with electrophilic metabolites. Here we extend the known landscape of PTMs with the identification of "lysine C(3)-iminylation," the conjugation of protein lysine residues with propionaldehyde. To stabilize iminylation for mass spectrometric analyses and distinguish it from other isomeric PTMs, we developed a fixation and stable-isotope...

Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial...

Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLG^(D257A)) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated...