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Summary Alzheimer's disease (AD) is an age-associated disease. Mutations in the amyloid precursor protein (APP) may be causative or protective of AD. The presence of two functionally redundant APP-like genes (APLP1/2) has made it difficult to unravel the biological function of APP during aging. The nematode Caenorhabditis elegans contains a single APP family member, apl-1. Here, we assessed the function of APL-1 on C. elegans' lifespan and found tissue-specific effects on lifespan by overexpression of APL-1. Overexpression of APL-1 in neurons causes lifespan reduction, whereas overexpression of APL-1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN-14 to preserve youthfulness. APL-1 lifespan extension also requires signaling through the FOXO transcription factor DAF-16, heat-shock factor HSF-1, and vitamin D-like nuclear hormone receptor DAF-12. We propose that reinforcing APL-1 expression in the hypodermis preserves the regulation of heterochronic lin-14 gene network to improve maintenance of somatic tissues via DAF-16/FOXO and HSF-1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved APP-related protein modulates aging.

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation. FOXO family members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) and negatively (e.g., ERK-MAPK, CDK2), with additional post-translational modifications further impacting on FOXO activity. Evidence has suggested that FOXOs behave as ‘ bona fide ’ tumour suppressors, through transcriptional programmes regulating several cellular behaviours including cell cycle arrest and apoptosis. However, an alternative paradigm has emerged which indicates that FOXOs operate as mediators of cellular homeostasis and/or resistance in both ‘normal’ and pathophysiological scenarios. Distinct FOXO family members fulfil discrete roles during normal B cell maturation and function, and it is now clear that FOXOs are aberrantly expressed and mutated in discrete B-cell malignancies. While active FOXO function is generally associated with disease suppression in chronic lymphocytic leukemia for example, FOXO expression is associated with disease progression in diffuse large B cell lymphoma, an observation also seen in other cancers. The opposing functions of the FOXO family drives the debate about the circumstances in which FOXOs favour or hinder disease progression, and whether targeting FOXO-mediated processes would be effective in the treatment of B-cell malignancies. Here, we discuss the disparate roles of FOXO family members in B lineage cells, the regulatory events that influence FOXO function focusing mainly on post-translational modifications, and consider the potential for future development of therapies that target FOXO activity.

The FoxO family of Forkhead transcription factors plays an important role in longevity and tumor suppression by upregulating target genes involved in stress resistance, metabolism, cell cycle arrest and apoptosis. FoxO transcription factors translate a variety of environmental stimuli, including insulin, growth factors, nutrients and oxidative stress, into specific gene-expression programs. These environmental stimuli control FoxO activity primarily by regulating their subcellular localization, but also by affecting their protein levels, DNA-binding properties and transcriptional activity. The precise regulation of FoxO transcription factors is enacted by an intricate combination of post-translational modifications (PTMs), including phosphorylation, acetylation and ubiquitination, and binding protein partners. An intriguing possibility is that FoxO PTMs may act as a ‘molecular FoxO code’ read by selective protein partners to rapidly regulate gene-expression programs. The effective control of FoxO activity in response to environmental stimuli is likely to be critical to prevent aging and age-dependent diseases, including cancer, neurodegenerative diseases and diabetes.

Histone methylation plays crucial roles in the development, gene regulation, and maintenance of stem cell pluripotency in mammals. Recent work shows that histone methylation is associated with aging, yet the underlying mechanism remains unclear. In this work, we identified a class of putative histone 3 lysine 9 mono/dimethyltransferase genes ( met-2, set-6, set-19, set-20, set-21, set-32, and set-33 ), mutations in which induce synergistic lifespan extension in the long-lived DAF-2 (insulin growth factor 1 [IGF-1] receptor) mutant in Caenorhabditis elegans . These putative histone methyltransferase plus daf-2 double mutants not only exhibited an average lifespan nearly three times that of wild-type animals and a maximal lifespan of approximately 100 days, but also significantly increased resistance to oxidative and heat stress. Synergistic lifespan extension depends on the transcription factor DAF-16 (FOXO). mRNA-seq experiments revealed that the mRNA levels of DAF-16 Class I genes, which are activated by DAF-16, were further elevated in the daf-2;set double mutants. Among these genes, tts-1 , F35E8.7 , ins-35 , nhr-62 , sod-3 , asm-2, and Y39G8B.7 are required for the lifespan extension of the daf-2;set-21 double mutant. In addition, treating daf-2 animals with the H3K9me1/2 methyltransferase G9a inhibitor also extends lifespan and increases stress resistance. Therefore, investigation of DAF-2 and H3K9me1/2 deficiency-mediated synergistic longevity will contribute to a better understanding of the molecular mechanisms of aging and therapeutic applications.

This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.

Elucidating how cell populations promote onset and progression of intervertebral disc degeneration (IDD) has the potential to enable more precise therapeutic targeting of cells and mechanisms. Single‐cell RNA‐sequencing (scRNA‐seq) is performed on surgically separated annulus fibrosus (AF) (19,978; 26,983 cells) and nucleus pulposus (NP) (20,884; 24,489 cells) from healthy and diseased human intervertebral discs (IVD). In both tissue types, depletion of cell subsets involved in maintenance of healthy IVD is observed, specifically the immature cell subsets – fibroblast progenitors and stem cells – indicative of an impairment of normal tissue self‐renewal. Tissue‐specific changes are also identified. In NP, several fibrotic populations are increased in degenerated IVD, indicating tissue‐remodeling. In degenerated AF, a novel disease‐associated subset is identified, which expresses disease‐promoting genes. It is associated with pathogenic biological processes and the main gene regulatory networks include thrombospondin signaling and FOXO1 transcription factor. In NP and AF cells thrombospondin protein promoted expression of genes associated with TGFβ/fibrosis signaling, angiogenesis, and nervous system development. The data reveal new insights of both shared and tissue‐specific changes in specific cell populations in AF and NP during IVD degeneration. These identified mechanisms and molecules are novel and more precise targets for IDD prevention and treatment. Intervertebral (IVD) cells maintain tissue structure and biomechanical function while their depletion and dysfunction are key mechanisms in IVD degeneration and back pain. Using scRNA‐seq, cell type and compartment‐specific are resloved and shared mechanisms and their transcriptional regulators that are dysregulated in disease. These findings define novel genes and gene regulatory networks that enable more precise therapeutic targeting for the prevention and treatment of intervertebral disc degeneration.

The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs ; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1 . To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs ; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer’s disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.

The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be ‘rejuvenated’ by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging stem cells.