Longevity Papers

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 induces Igf2 expression, which is essential for regeneration. Notably, this regenerative response is defective in aged mice but can be restored by ectopic Igf2 expression. As a hormone, circulating IGF2 can compensate for local deficiencies in response to organ-restricted perturbations, whereas whole-body Hippo activation or Igf2 deletion results in small mice with miniature organs. Hence, the Hippo-IGF2 axis is a general regulator of growth and organ size during development and regeneration.

Cellular senescence involves progressive acidification, but how cells sense and adapt to this pH shift remains unclear. Here we report that metabolic enzyme GOT1 functions as a pH sensor that undergoes liquid-liquid phase separation (LLPS) to combat senescence. Proteomic analysis identified GOT1 upregulation in aged human lung cells. Acidic conditions mimicking senescence directly induce GOT1 LLPS via its N-terminal intrinsically disordered region (IDR1), recruiting ME1 to form dynamic enzymatic co-condensates that scavenge reactive oxygen species and alleviate oxidative stress. To quantitatively interrogate GOT1's pH microenvironment during senescence, we engineered BDP-PLP, a first-in-class fluorescent probe conjugating the native GOT1 cofactor pyridoxal phosphate to a BODIPY fluorophore. Operating via a binding-inhibited PET mechanism, this probe enables high-specificity GOT1 targeting and pH-dependent fluorescence lifetime imaging (FLIM). Using FLIM, we achieved quantitative real-time visualization of pH dynamics within GOT1 condensates in living cells, revealing that phase separation generates a highly acidic local microenvironment critical for its anti-senescence function. This study uncovers a pH-triggered phase separation mechanism that bolsters antioxidant defense via metabolic enzyme co-condensation, offering new perspectives on metabolic adaptation in aging and establishing a chemical tool for probing microenvironmental dynamics.

Biological aging is accompanied by systematic changes in epigenetic modifications and chromatin organization. The reversal of the effects of aging, rejuvenation, is experimentally achieved by the transient induction of factors that modify these marks in cells and organisms. Here, we show that key features of rejuvenation experiments emerge from the biophysical interplay between dynamic epigenetic marks and the three-dimensional conformation of chromatin. Using a minimal field theory and molecular dynamics simulations, we show that the system responds in three distinct temporal regimes. The intermediary regime fulfills necessary conditions for successful rejuvenation. In this regime, the system spends time near a separatrix, allowing for high epigenetic plasticity, while memory retained in the chromatin conformation enables restoration of the original epigenetic correlations. Analysis of sequencing data further supports the predicted coupling between chromatin compaction and epigenetic correlations. Our results provide a physical explanation for how rejuvenation may remodel age-associated epigenetic states without irreversibly erasing cellular identity. We identify a general mechanism by which memory stored in a slow structural variable permits reversible remodeling of a faster internal state.

Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney aging using IRAP knockout mice, as well as in wildtype mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate declined by 25% in wild-type mice between 3-23 months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis and accumulation of senescent cells in the proximal tubules of the kidney. IRAP knockout mice were protected against age-related decline in glomerular filtration rate, renal fibrosis and senescence burden compared to age-matched wildtype mice. IRAP inhibition for 4 weeks (HFI-419, 500 ng/kg/min) in 28-month-old wild-type mice similarly prevented age-related decline in glomerular filtration rate and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.

Given the increasing focus on natural interventions for healthy aging, this research evaluates the longevity-promoting potential of egg-derived peptides (EPs) extracted from American shad (Alosa sapidissima). Using Caenorhabditis elegans as the experimental model, researchers found that 0.15 mg/mL EP supplementation extended lifespan by a remarkable 33.33%. EP also significantly enhanced healthspan, improving physiological metrics such as head thrashing, body bending, and pharyngeal pumping by 24.37%, 22.33%, and 28.81%, respectively. Furthermore, EP reduced aging biomarkers-including lipofuscin and reactive oxygen species (ROS)-by up to 40.34%, while boosting overall antioxidant capacity (SOD increased by 53%, MDA decreased by 30.76%). Transcriptomic analysis identified 2196 differentially expressed genes (DEGs) out of 23 057 total identified genes, providing deep insights into the mechanisms underlying EP-mediated longevity. Crucially, EP upregulated genes responsible for unsaturated fatty acid biosynthesis (fat-7 and elo-4) to optimize cell membrane fluidity. Conversely, it downregulated genes linked to fatty acid β-oxidation (acs-2, acox-1.5, ech-9, hacd-1) and endogenous stress responses (sod-3, hsp-16.1, hsf-1). Validated via qRT-PCR, these shifts indicate that EP extends lifespan by fundamentally remodeling lipid metabolism and maintaining redox homeostasis. Ultimately, these findings highlight EP as a highly promising functional food ingredient for promoting healthy aging.

Cellular senescence, a hallmark of aging, entails the irreversible cessation of cell division in response to intrinsic and extrinsic stressors. Though metabolically active, senescent cells lose their replicative capacity and resist apoptotic signals, accumulating tissues with advancing age and contributing to age-related pathologies. Senescence is characterized by the acquisition of a senescence-associated secretory phenotype (SASP), releasing a myriad of bioactive molecules. SASP not only influences intracellular processes but also orchestrates the modification of neighboring cells and the surrounding microenvironment. In the context of aging, the proportion of senescent cells escalates, ranging from 1 to 15% in different species, tissues, and activity levels. This accumulation is associated with age-related diseases and morbidity. Beyond aging, senescence induction is observed in response to cancer treatments, including radiotherapy and chemotherapy, potentially contributing to cancer metastasis and recurrence. Consequently, the exploration of senolytic therapies aimed at eliminating senescent cells has gained considerable momentum. Addressing the limitations of free therapeutics, nano-drug delivery systems have been meticulously engineered to enhance solubility, stability, and targeted delivery. These nanocarriers overcome challenges related to poor bioavailability, uncontrolled biodistribution, and off-target effects, thereby improving therapeutic efficacy and safety. Precise control over nanoparticle size and uniformity enables targeted distribution, enhancing therapeutic precision. While nanomedicine is revolutionizing healthcare, its potential to mitigate cellular senescence remains largely unexplored despite extensive cancer research. This comprehensive review aims to consolidate the current understanding of cellular senescence and its pathological consequences. Furthermore, we present an in-depth analysis of studies employing nano-drug delivery systems in cellular senescence research, emphasizing their potential role and prospects in this evolving scientific landscape. This research is a significant step towards filling this gap and paving the way for future advancements in the field.

Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.

Ageing research has undergone a paradigm shift from descriptive theories to a mechanistic understanding grounded in the interconnected biological processes. This work synthesizes the current landscape of ageing research, emphasizing the critical role of biomarkers in translating mechanistic insights into clinical application. Biomarkers, ranging from molecular and cellular markers to functional and imaging parameters, serve as essential tools for quantifying biological age, assessing the efficacy of therapeutic interventions, and predicting age-related disease risk. However, rather than offering another catalogue of hallmarks or isolated biomarker classes, this work structures the field through a translational decision framework that connects mechanistically grounded, organ-specific biomarkers to therapeutic evidence levels, participant stratification, longitudinal response tracking, and safety evaluation. Within this framework, we distinguish interventions targeting ageing biology from those directed at established age-related diseases, critically assess insights from inconclusive or negative human trials, and delineate essential prerequisites for biomarker qualification and clinical adoption. Despite significant challenges, such as the lack of a universal gold standard biomarker and discrepancies between preclinical models and human biology, the continued development and validation of robust biomarker systems are imperative. As the field moves toward next-generation composite biomarkers and multi-target combination therapies, biomarkers will be indispensable for driving the paradigm shift from treating age-related diseases to proactively managing the ageing process itself, ultimately paving the way for clinical-grade anti-ageing interventions.

We develop an integrated, high-throughput platform to evaluate pharmacological lifespan-extending interventions across five model organisms spanning unicellular to mammalian biology including yeast, nematodes, fruit flies, killifish, and mice. By combining automated imaging, miniaturized assays, and deep-learning-based death detection, we evaluate over 400 compounds across thousands of conditions. In S. cerevisiae, a miniaturized PI/flow cytometry CLS assay enables scalable screening and identifies key assay confounders, while in C. elegans and D. melanogaster, compact imaging platforms coupled to YOLO-based detection provide a no-transfer, high-throughput survival scoring, and capture compound-, diet-, and sex-dependent effects. In killifish, we develop an in-house drug-pellet formulation for standardized oral delivery in large cohorts, and in mice we combine longitudinal lifespan studies with home-cage activity monitoring to assess late-life interventions. Cross-species integration identifies multi-species geroprotectors and reveals convergence on known and novel conserved longevity pathways, illustrating how this scalable framework can prioritize interventions with high translational potential.