Aging & Longevity

CONCLUSION: Translational development faces several barriers, including poor blood-brain barrier (BBB) penetration, off-target neurotoxicity, uncharacterised long-term safety and limited generalisability from APP/PS1 models lacking tauopathy. All MERCS-targeted and senolytic combinatorial strategies discussed herein represent prospective pre-clinical research directions rather than mature clinical therapeutic approaches. We propose an experimental roadmap based on conditional knockouts,...

With accelerating population aging, age-related bone loss, osteoporosis, and delayed bone defect repair have become major challenges in regenerative medicine. Bone aging is not caused by the decline of a single cell type, but is a multilevel pathological process driven by the continuous coupling and mutual reinforcement of intracellular damage accumulation, senescence signal propagation, and microenvironmental deterioration. Based on established aging theories, this review integrates...

Working memory is one of the core cognitive functions that declines in older adulthood. Brain reserve (BR) refers to neurobiological status of the brain that supports cognition, offering a valuable neurostructural framework for understanding working memory decline among older adults. However, most existing studies rely on gross, whole-brain measures of BR which may lack sensitivity to specific cognitive functions, and few studies have examined their sex differences. Based on 131 healthy older...

Cardiovascular ageing is accompanied by progressive impairment of redox buffering, mitochondrial quality control, proteostasis and metal homeostasis. Iron and copper homeostasis, together with cystine-glutathione and thiol/disulfide redox metabolism, are increasingly recognized as interconnected determinants of metabolic vulnerability and regulated cell death (RCD) in age-related cardiovascular diseases. Ferroptosis, defined by iron-dependent lipid peroxidation and impaired anti-peroxidative...

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...

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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...

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...

Photochemical oxidation in the aqueous phase is critical for chemical evolution of secondary organic aerosols (SOA), but it represents one of the most uncertain processes in aerosols and clouds. Here, we show that photoirradiation of SOA derived from biomass burning precursors leads to substantial formation of superoxide. The combination of laboratory measurements and kinetic modeling reveals that superoxide generation is driven by photosensitization reactions in aromatic SOA, while the dominant...

Seed longevity (SL) is vital for ensuring food security worldwide. However, the genetic basis of SL has been scarcely documented. Here, we report the cloning of a major SL locus, qSL6, encoding a fatty acyl-ACP thioesterase type B. SL6 is functionally conserved in regulating palmitic acid synthesis in seeds, conferring higher oxidation durability and SL in various species. Through the VP1-SL6 module, a seed desiccation-derived ABA signal is transmitted via VP1, which directly activates SL6...

INTRODUCTION: Population ageing has increased the prevalence of dementia, often accompanied by mobility impairments. It is essential to develop effective interventions and promote adherence among people with dementia. Culturally meaningful activities may enhance motivation, engagement, and rehabilitation outcomes.