Longevity Papers

Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.

To discover novel mechanisms, we compared changes in redox metabolism markers induced by caloric restriction (CR) and sulfur amino acid restriction (SAAR).

Single-celled organisms grown in identical conditions have variable life spans. Identifying the factors that drive the inherent variability in life span is crucial for our understanding of aging at a fundamental level. Here, we revisit the role of chromosome XII instability as a source of life span variability in aging populations of the budding yeast, Saccharomyces cerevisiae. We followed populations of mother cells as they aged and quantified changes in karyotype, DNA content, and aberrant structures within the rDNA. We quantified the kinetics of rDNA amplification both as extrachromosomal rDNA circles (ERCs) and as structural forms that are not resolved on CHEF gels. We propose mechanistic models of rDNA instability that describe how both ERCS and other aberrant structures are generated and the unique affects they have on life span. One of the models, which we call Catastrophic IntraChromosomal Repair (CICR), follows the fate of a broken replication fork in the rDNA locus when the template used for repair has already been replicated. At the completion of replication, when all other replication forks have successfully terminated, single, unopposed replication forks remain in the rDNA generating branched DNA molecules that have profound consequences during mitosis and/or subsequent cycles. In addition to ERCs, CICR and related events are additional forms of rDNA instability that contribute to the life span variability in isogenic populations of aging yeast.

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.

Arsenic is a naturally occurring metalloid, and its pollution poses a global threat to humanity. Studies have shown that arsenic exposure accelerates aging, but the effects and mechanisms of sodium arsenite exposure on aging across both parental and offspring remain unclear. In this study, we investigated the effects of sodium arsenite on lifespan, locomotion, heat tolerance, antioxidant defense systems, autophagy, and the insulin/IGF-1 signaling (IIS) pathway in Caenorhabditis elegans (C. elegans). Initially, exposure from the L1 to L4 larval stage to 100 μM or 200 μM sodium arsenite significantly shortened the lifespan of C. elegans. Sodium arsenite also reduced body length, body width, head-swing frequency, and heat-stress resistance. It also reduced superoxide dismutase (SOD) activity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation in C. elegans parents and offspring. qRT-PCR analysis showed that sodium arsenite exposure activated the IIS pathway in C. elegans parents and offspring by upregulating the upstream genes age-1 and daf-2 and downregulating the downstream transcription factor daf-16. Concurrently, it reduced the mRNA levels of bec-1, lgg-1, and sod-3, indicating impaired autophagy and reduced DAF-16 activity. Furthermore, sodium arsenite exposure diminished the fluorescence intensity of LGG-1::GFP in the DA2123 strain and SOD-3::GFP in the CF1553 strain across both generations, consistent with the qRT-PCR results. To further investigate the role of autophagy, we treated worms with rapamycin, which alleviated the pro-aging effects of arsenite in both generations. Therefore, our results show that sodium arsenite exposure accelerates aging in both parental and offspring C. elegans, a process linked to the IIS pathway, oxidative stress, and autophagy.

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.