Longevity Papers

Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms underlying HSPC aging is essential for developing strategies to alleviate age-related dysfunction. Here, we identify angiopoietin-like 8 (ANGPTL8), a secreted glycoprotein known for its role in glucose and lipid metabolism, as a novel regulator of HSPC aging. Systemic ANGPTL8 knockout significantly attenuated senescence-associated phenotypes in multiple murine tissues. In vitro and in vivo analyses of proliferation, colony-forming capacity, mitochondrial membrane potential, senescence-associated secretory phenotype (SASP) expression, reactive oxygen species (ROS) accumulation, myeloid skewing, and early hematopoietic regeneration further demonstrated that ANGPTL8 promotes HSPC aging. Mechanistically, ANGPTL8 deficiency activated the PI3K/AKT signaling pathway, whereas a PI3K activator rescued the senescence effects induced by recombinant ANGPTL8 (rANGPTL8). Furthermore, co-immunoprecipitation (Co-IP) confirmed that rANGPTL8 directly interacts with the transmembrane receptor PirB. Recombinant PirB (rPirB) reduced the phosphorylation of PI3K/AKT, whereas PirB knockdown effectively blocked the inhibitory effect of rANGPTL8 on PI3K/AKT phosphorylation. Collectively, our findings suggest that ANGPTL8 drives HSPC aging primarily by suppressing the PI3K/AKT pathway via its receptor PirB, providing a new potential target to alleviate the aging of HSPCs.

Aging biology still lacks a fully mechanistic explanation for why functional decline accelerates after sexual maturity in the absence of a single initiating pathology. Here, we integrate cross-species epigenetic, transcriptomic, and proteomic datasets to test whether aging is associated with a post-maturity imbalance between two genome partitions: housekeeping genes (HG), which encode the cellular maintenance infrastructure, and integrative genes (IntG), which support specialized tissue functions. We emphasize HG because this compartment defines the basal capacity for repair, proteostasis, biosynthesis, and cell-autonomous survival; changes in HG output may therefore help distinguish candidate upstream regulatory changes from downstream damage signatures. Across datasets, we observe a consistent divergence after sexual maturity: the HG compartment loses transcriptional share in low-renewal tissues, whereas IntG promoter methylation becomes progressively more dispersed, with methylation-mRNA Spearman correlations of rho = -0.15 to -0.28 (five tissues, p < 0.05 FDR) and modest mRNA-protein concordance (rho = 0.204, p < 0.001, n = 6,449), indicating partial post-transcriptional decoupling. These associations are compatible with the continued action of an ontogenetic regulatory program that shifts genome activity toward specialized function at the expense of maintenance. This interpretation is consistent with hyperfunction/developmental theories, while reframing the hyperfunctional state as a possible downstream consequence of asymmetric developmental regulation. Although causality remains to be tested experimentally, the convergence of multi-omics evidence supports a testable model in which restoring HG/IntG regulatory balance may represent a future experimental direction for modulating age-related decline, rather than a translational implication supported by the current data.

Body-brain communication is crucial for optimal neuronal performance across the lifespan, yet whether peripheral organs regulate spinal cord motoneuron (MN) function through circulating molecules remains unknown. The expression of hormone receptors by spinal MNs raises the possibility that circulating cues allow the spinal cord to sense the body's energetic state and sustain motor activity. Here, we show that the bone-derived hormones osteocalcin (OCN) signals on spinal MNs via its receptor GPR158. GPR158 is selectively enriched in spinal cholinergic MNs, and its loss, globally or specifically in spinal MNs, or the one of OCN, impairs locomotor function and reduces choline acetyltransferase (ChAT) levels. Mechanistically, OCN signaling through GPR158 fine-tunes autophagy, mitophagy and mitochondrial activity in spinal MNs. Restoring any of these processes, by pharmacologically inducing mitophagy or chemogenetically activating mitochondria, is sufficient to rescue the locomotor deficits of Gpr158-deficient mice. Finally, OCN restoration in aged mice reverses age-related locomotor decline through a mechanism that requires MN autophagy and mitophagy. This study reveals that through OCN, the skeleton influences motor functions by fine-tuning motoneuronal mitochondria, and suggests that age-related motor decline is, at least in part, reversible.

The extraordinary lifespan variation in domestic dogs provides a natural experiment for testing how intrinsic rates of biological aging shape lifespan. Using 1640 methylomes from 894 dogs, we developed an epigenetic clock that predicted mortality and demonstrated that epigenetic aging is fastest early in life. At orthologs of human age-associated genes, dogs exhibited concordant age effects on promoter methylation, highlighting conserved remodeling of immune pathways. We found that larger and male dogs, which are shorter lived, exhibit accelerated molecular aging. Distinct epigenetic architectures mediated these effects: Sex-dependent methylation changes were concentrated on the X chromosome, whereas size-associated methylation was especially pronounced at transposable elements (TEs). These findings show that epigenetics reflects lifespan differences in dogs and identifies TEs as potential mediators of size-associated lifespan.

Aging is driven by multiple factors such as mitochondrial dysfunction and oxidative stress, leading to various age-related diseases. Phosphodiesterase-4 (PDE4) is a subfamily of phosphodiesterases and specifically hydrolyzes cAMP. PDE4 inhibitors have been approved for the treatment of several diseases and shown to improve aging-related conditions. However, the precise effects and underlying mechanisms of PDE4 inhibitors on lifespan and cellular senescence remain unclear. Here, we report that two PDE4 inhibitors (roflumilast and rolipram) extend C. elegans lifespan and that roflumilast attenuates passage-induced cellular senescence in mouse embryonic fibroblasts (MEFs). We further demonstrate that protein kinase A (PKA) activation mediates PDE4 inhibitors' anti-aging effects by improving mitochondrial function and alleviating oxidative stress, and that the mechanism is conserved in C. elegans and MEFs. Our findings provide evidence that PDE4 inhibitors possess anti-aging potential.

Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.

Cellular senescence contributes to age-associated tissue dysfunction through persistent growth arrest, metabolic remodeling, and altered communication with immune and stromal cells. Senolytic therapies preferentially eliminate susceptible senescent cells, while senomorphic therapies modulate harmful senescence-associated activities. Nanoparticle engineering can improve the delivery of these agents through cargo protection, surface functionalization, and controlled release. Surface ligands can promote cellular uptake, and components responsive to lysosomal β-galactosidase, acidic pH, reactive oxygen species, or protease activity can regulate cargo release. The selectivity of these mechanisms depends on biological features that vary among senescent populations and also occur in other cellular states. This review examines how material composition and physicochemical properties influence target recognition, intracellular transport, therapeutic activity, and safety. Representative platforms are evaluated across fibrotic, musculoskeletal, metabolic, oncologic, and neurodegenerative disease models, with particular attention to mitochondrial delivery, immune-mediated clearance, nucleic-acid modulation, and microbiome interactions. Preclinical findings are considered alongside human senotherapy studies, which have primarily evaluated small-molecule drug regimens and yielded preliminary or mixed outcomes. Clinical development requires reproducible manufacturing, pharmacokinetic characterization of both carrier and cargo, and assessment of immunotoxicity and delayed organ injury in older hosts. Progress depends on matching a defined pathological cell population to an appropriate delivery strategy and demonstrating an advantage in therapeutic index or sustained functional outcomes against relevant comparators, including clinically feasible non-nanoparticle treatments where available.

Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

Population aging drives a parallel increase in muscle atrophy and cognitive decline, two major causes of disability in older adults. Mitochondrial dysfunction and chronic inflammation are core drivers of aging, with pyroptosis serving as a critical link between them. However, conventional single‑technique approaches capture only fragmented, static information and fail to bridge molecular events with whole‑organism phenotypes. This review introduces a unique integrative perspective that weaves established multimodal technologies ranging from molecular interaction analysis and absolute quantification to cellular metabolic and electrophysiological recordings, tissue clearing and laser microdissection, and finally to in vivo imaging and body composition analysis into a coherent, cross‑scale chain of evidence. By applying this paradigm to the mitochondria‑pyroptosis axis, we reveal how oxidative mitochondrial DNA enhances NLRP3 binding, how aged cells exhibit metabolic vulnerability and electrophysiological susceptibility, how pyroptotic hotspots form with spatial heterogeneity in tissues, and how pyroptosis signals quantitatively correlate with the decline in muscle mass and cognitive function. The core contribution of this review is the methodological framework of multimodal integration that enables causal tracing from molecular triggers to functional outcomes. This paradigm offers a transferable strategy for dissecting complex aging mechanisms and provides a theoretical foundation for targeting the mitochondria‑pyroptosis axis in precision anti‑aging interventions.

Cellular senescence, a key feature of ageing, involves irreversible cell cycle arrest and the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors, which contribute to tissue degeneration and age-related diseases. Targeting senescent cells with senolytics, senomorphics and anti-ageing therapies marks a major shift in translational geroscience, with the potential to delay or reverse age-related conditions. A systematic review and narrative synthesis was conducted in accordance with PRISMA 2020 guidelines. Eligible human clinical studies evaluating pharmacological interventions targeting cellular senescence were included, comprising randomized and nonrandomized clinical trials and pilot studies reporting clinical, functional or senescence-associated outcomes. Data on study characteristics, interventions, efficacy, safety and senescence-associated biomarkers were extracted and synthesized qualitatively. Six completed clinical studies were included in the evidence synthesis, with one additional ongoing clinical trial identified separately. Senolytic interventions, particularly dasatinib plus quercetin, showed preliminary improvements in selected functional outcomes and reductions in senescence-associated biomarkers, while senomorphic and mTOR-targeting interventions demonstrated effects on selected tissue and immune-related outcomes. Reported adverse events were generally mild or manageable, but small sample sizes and short follow-up limited assessment of uncommon and long-term safety risks. Current evidence suggests that pharmacological targeting of cellular senescence is feasible and may produce measurable biological and functional effects in humans, but evidence remains insufficient to establish clinical efficacy or long-term safety. Senolytic and senomorphic strategies should therefore be considered investigational rather than established therapies. Larger, adequately powered randomized trials with standardized senescence biomarkers, clinically meaningful outcomes, longer follow-up and systematic safety assessment are needed.

Aging disrupts neural function, but whether impaired noradrenergic control of brain metabolism contributes to functional decline remains unclear. Using genetically encoded fluorescent sensors we measured metabolic and signaling responses in neurons and glia of living Drosophila brains following stimulation with octopamine, the invertebrate analogue of noradrenaline. Aging was accompanied by neurodegeneration, reduced locomotion and enhanced oxidative whole-brain metabolism. Octopamine increased D-glucose uptake selectively in astrocytes and elevated L-lactate in both astrocytes and neurons, consistent with astrocytic glycolysis coupled to neuronal L-lactate uptake; monocarboxylate transporter inhibition caused selective astrocytic L-lactate accumulation. In aged animals octopamine-evoked metabolic responses in astrocytes and neural Ca2+ transients were markedly reduced. This impairment was associated with lower expression of adrenoceptor-like tyramine 1 receptor (Tyr1R). Selective Tyr1R overexpression in (nor)adrenergic-like Tdc2 neurons prolonged lifespan, restored Ca2+ signalling and improved locomotor performance. These findings identify Tyr1R-dependent Ca2+ signalling as an age-sensitive regulator of brain metabolism and motor function.

DE-SWAN is a commonly used method to study how large ensembles of omics biomarkers change across the life course. It has been used to demonstrate apparent repeated accelerations and decelerations of aging rates across the life course, including 2-3 peaks of aging-related changes. This result contradicts what is expected based on the demography of aging and known biological mechanisms. Here, we use simulations to study the robustness of DE-SWAN to the age distribution of the study sample and to choice of window size. We show that under many realistic scenarios, DE-SWAN is highly sensitive to factors unrelated to the underlying rates of change in aging biology. This calls into question the results of previous analyses that have attributed DE-SWAN peaks to acceleration and deceleration of aging. We conclude that the method is unreliable for studying rates of change across the life course under most circumstances.