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Cellular senescence is a state of durable cell cycle arrest after a defined number of cell divisions. The number of population doublings of normal cells in culture depends on the species but not on the types of cells used to establish the culture, showing a positive correlation with the life span of the animals. Therefore, the results suggest a physiological link between a limited proliferative capacity in cell culture and the processes observed in organismal aging. The pivotal role of senescence in organismal aging and the onset of age-related disorders, such as atherosclerosis, type II diabetes, and Alzheimer's disease, is supported by the observation that the clearance of p16-positive senescent cells delays various age-associated disorders and extends healthy lifespan. In this review, I provide an overview of recent advances in understanding the mechanisms underlying the induction of senescence and maintenance of the specific phenotypes, such as senescence associated secretory phenotypes (SASP).

Over the past 15 years, many studies have revealed that Wnt signaling has a strong impact on hematopoietic stem cell fate. After a controversy over the interpretation of some results, the current understanding is that an appropriate degree of canonical Wnt signaling induces hematopoietic stem cell self-renewal and that noncanonical Wnt signaling keeps the quiescence. It is also likely that the balance between canonical and noncanonical Wnt pathways regulates the stress response and aging of hematopoietic stem cells.

Aging and senescence are main topics in this ASBMR Annual Meeting as both the Aurbach lecture and Avioli award lecture focused on the topic. Osteoporosis is one of typical age-related disease and elimination of senescent cells is new strategy of treatment for osteoporosis. Antibody and synthetic antagonist or agonist which modify the action of hormone and growth factor, an inhibitor of ectopic bone formation and a stimulator of muscle mass have been developed as a new drug for metabolic bone diseases and skeletal dysplasias.

The frequency of clonal hematopoiesis in humans vastly increases with aging. Older adults may develop one or several clones and this condition is called clonal hematopoiesis of indeterminate potential (CHIP). Recent genetic analyses have identified the genes inducing CHIP. These mutant genes are detected frequently in elderly people and this condition is a precursor of hematopoietic neoplasms. The prevalence of hematopoietic neoplasms in patients with CHIP is tenfold that in those without CHIP. Consequently, the mechanism of aging and leukemogenesis of hematopoietic stem cells is being understood. Furthermore, the efficacy of senolysis, selectively removing scenescent cells from tissues, has been demonstrated in mice. The clinical application of senolysis is anticipated shortly.

Recently, it has been found that systemic metabolic disorders are associated with the onset and progression of various joint diseases. Although osteoarthritis(OA)is mainly a degradative condition of the articular cartilage induced by mechanical stress, there is a growing body of data demonstrating the involvement of metabolic factors including fat metabolism. Recent studies have revealed that adipokines including adiponectin and leptin are associated with inflammation of rheumatoid arthritis. A better understanding of these relationships may lead to new strategies to treat or prevent joint disease such as OA.

Bones support the body as part of the human musculoskeletal system. They also contain bone marrow, which is a site of hematopoiesis. Bone marrow mesenchymal stem cells play a vital role by regulating skeletal tissue formation and maintaining hematopoiesis. While the presence of bone marrow-derived mesenchymal stem cells has been indicated, they have yet to be fully understood in vivo. Recent studies using genetic mouse models revealed that perivascular stromal cells function as mesenchymal stem cells, and their differentiation status may vary during the early stage of life to adulthood. Furthermore, studies have investigated the underlying mechanisms that regulate the cell fate decision of mesenchymal stem cells. These findings could lead to the design of new therapeutic approaches for metabolic bone disease and hematopoietic disease.

Cellular senescence is a state of irreversible cell proliferation arrest provoked by a persistent DNA damage induced by a variety of potentially oncogenic signals, and it functions as a primary tumor-suppression mechanism. Recent studies, however, revealed that senescent cells have the potential to secrete numerous inflammatory cytokines, chemokines, growth factors and matrix-remodeling factors, since unlike apoptotic cells, senescent cells are viable for a long period of time. This newly identified phenotype of cellular senescence, called senescence-associated secretory phenotype(SASP or senescence-associated secretome), could potentially provide beneficial effects, such as tissue repair, but sometimes could induce deleterious side effects, such as cancer progression, depending on the biological context.

Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.

The hair follicle is a complex miniorgan of the skin and undergoes cycles of growth(anagen), apoptosis-mediated regression(catagen)and rest(telogen). Regeneration of the new hair shaft dependent on the activation of hair follicle stem cells(HFSCs), harboured in the bulge region. Using a hair follicle model, some molecular players that control the balance between HFSC maintenance and ageing-associated HFSC dysfunction have been identified. Here, we reviewed and discussed the recent findings of molecular characterization of HFSCs biology and pathology.

Articular cartilage is an important structure contributing to shock absorption and joint lubrication. Aging and trauma cause loss of function of articular cartilage, resulting in osteoarthritis(OA). Chondrocyte, the only type of the cell that resides in the articular cartilage. Recent studies have revealed that aging-associated changes in chondrocytes are important causative factors of OA. This review describes various mechanism and factors involved in aging of articular cartilage and chondrocytes.

Protein p53 is described as guardian of the genome contributing for the suppression of tumorigenesis. p53 is also known to be the critical regulator of cellular senescence. It is activated by various genomic stresses including telomere attrition, excessive mitogenic sig- naling and genotoxic agents(eg. reactive oxygen species), and mediates cellular senescence. Senescent cells develop growth arrest, associated with altered gene profiles. These changes induce chronic inflammation and organ dysfunction, promoting pathologies in age related disorders. In this review, we delineate the role of p53 induced cellular senescence in age related disorders, such as obesity/diabetes and heart failure.

In addition to the discovery that mature cells can be reprogrammed to become pluripotent stem cells(iPS cells), the technical innovations of big-data analyses as well as the cutting- edge technologies such as nuclear reprogramming technique and genome-editing system are emerging a big paradigm shift in the field of regenerative medicine and aging. This is bonafide a kind of the molecular biological movement of the Renaissance to answer the question of 120 years ago "D'ofi Venons Nous Que Sommes Nous Oi Allons Nous", a testament of Paul Gauguin. These technologies enable us, particularly inexhaustible researchers with challenging spirits, not only to dynamically, qualitatively and visually systematically understand underling mechanisms of single gene, single molecule, single cell and their complicated networks in vivo with broadly combining them from cells to organs and individuals', but also to pursue the mechanistic insight into "Life, Aging, Disease, and Death" and thereby con- trol them. We herein review about recent hot topic findings focused on regenerative medicine, cellular senescence & aging as well as aging-related disease, and then discuss the functional interconnection between reprogramming process and senescence signal.

Individual variability is one of the common features of aged human populations. As the popu- lation aging rate in Japan is forecasted to be over 40 % around 2050, physiological and patho- logical variability of aging is a rising big issue not only for medical scientist but also as social concerns. Such variability could be partly explained as consequences of human evolution, but decrease of death rates also facilitates it indirectly. Here we review on aging and anti- aging research in 21st century, which would play a significant role to dissolve the problems relevant to the following issues. That is, regulation of aging, epigenetics, removal of senescent cells, regeneration of the tissues, and environmental improvement.

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) exhibit accelerated aging phenotypes, which are caused by mutations in the LMNA or WRN genes, respectively. Accumulating evidence suggested that the mutations commonly caused senes- cent phenotypes such as DNA damage, cell cycle arrest, nuclear enlargement and nuclear shape abnormality. Furthermore, both mutations showed significant loss of nuclear lamina -binding proteins, a heterochromatin protein, and an epigenetic H3K9me3 mark in hetero- chromatin loci. These biochemical deficits might explain common molecular mechanism underlying the pathogenesis of the progeria.

Why do we age, and how do we age ? There have been more than hundreds of theories of aging that attempt rational explanation for these challenging questions. From an evolu- tionary viewpoint, genetic trade-off between longevity and fecundity could explain the evo- lution of aging. Recent applications of new experimental methods and techniques to aging research provided mechanistic insights into the role of oxidative stress, mitochondrial dys- function, cellular senescence, and modulation of the insulin/insulin-like growth factor sig- naling and NAD+-dependent deacetylase sirtuins in aging process. In this article, a long history of aging research is looked back on, and the concepts and theories of aging are summarized.

Kidney is an energy-consuming organ and its function deteriorates according as aging. Various mechanisms for cellular senescence and organ aging have an impact on the initiation and progression of CKD, which includes telomere attrition, genomic instability, stem cell exhaustion, mitochondrial dysfunction, impaired nutrient signaling, inactivation of Sirtuin or Klotho-mediated pathway and renin-angiotensin system activation. Interventions in these pathways have provided therapeutic strategy against CKD. On the other hand, renal dys- function, in turn, affects human aging process. Because of this close relationship between human aging process and CKD, aging phenotype, such as frailty can be used as a clinical marker of the prognosis of CKD as well as of other age-related diseases including cardio- vascular disease and type II diabetes. Amelioration of this aging phenotype can provide a novel therapeutic strategy against CKD for the purpose of providing CKD patients with suc- cessful aging.

Chronic arsenic exposure is associated with many diseases, including cancers. Our study using in vivo assay in gpt-delta transgenic mice showed that arsenic particularly induces G : C to T : A transversions, a mutation type induced through oxidative-stress-induced 8-OHdG formation. Gestational arsenic exposure of C3H mice was reported to increase hepatic tumor incidence. We showed that gestational arsenic exposure increased hepatic tumors having activated oncogene Ha-ras by C to A mutation. We also showed that DNA methylation status of Fosb region is implicated in tumor augmentation by gestational arsenic exposure. We further showed that long-term arsenic exposure induces premature senescence. Recent studies reported that senescence is involved in not only tumor suppression, but also tumorgenesis. All these effects of arsenic might be involved in arsenic-induced carcinogenesis.

Vascular calcification is an independent risk factor for the development of cardiovascular disease and is classified into two types based on the site of calcification : intimal atherosclerotic calcification and Mönckeberg's medial calcification. Matrix vesicles released from macrophages and vascular smooth muscle cells (VSMC) during apoptosis play a pivotal role in formation of fine granular calcification, while osteogenic differentiation of VSMC contributes to progression of advanced calcification. Recent noninvasive imaging studies of atherosclerotic calcification provide robust evidence that inflammation precedes active calcification, leading to establish the inflammation-dependent calcification paradigm. On the other hand, elastin degradation by increased elastolytic activities and disturbance of regulatory systems of extracellular pyrophosphate metabolism play an important role in development of Mönckeberg's medial calcification.

Aging is associated with impairment of various circadian rhythms of body, including daily rhythms of blood pressure, core body temperature, and the sleep-waking cycle. In mammals circadian rhythmicity is under control of molecular pacemaker that is composed of products of clock genes. Recent evidence suggests that cellular senescence impairs circadian rhythmicity and contributes to various age-associated diseases. Senescence decreases the ability of cells to transmit circadian signals such as nitric oxide to their clocks. The regulation of clock gene expression may be a novel strategy for treatment of age-associated impairment of circadian rhythmicity.

It has recently become apparent that obesity is associated with chronic inflammation and several common types of cancer development. Although several events were proposed to be involved in these pathologies, the precise mechanisms underlying obesity-associated inflammation and cancer largely remain unclear. Here, we show that senescence-associated secretory phenotype (SASP) plays crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of a bacterial metabolite that cause DNA damage. The enterohepatic circulation of the bacterial metabolites provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn, secretes various inflammatory and tumour promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Importantly, reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the induction of SASP by the gut bacterial metabolite in HSCs plays key roles in obesity-associated HCC development. Interestingly, moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis (NASH), implying that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer.

Cell proliferation is regulated through a transition between the G0 phase and cell cycle. We isolated a mammalian temperature-sensitive mutant cell line defective in the function from the G0 phase to cell cycle. Senescent human somatic cells fail to enter into the cell cycle from the G0 phase with stimulation by any growth factor. Telomere shortening was found to be a cause of cellular senescence, and reexpression of telomerase immortalized human somatic cells. Immortalized human somatic cells showed normal phenotypes and were useful not only for basic research but also for clinical and applied fields. The importance of p53 and p21 activation/induction i now well accepted in the signal transduction process from telomere shortening to growth arrest, but the precise mechanism is largely unknown as yet. We found that the MAP kinase cascade and histone acetylase have an important role in the signaling process to express p21. Tumor tissues and cells were found to have strong telomerase activity, while most normal somatic human tissues showed very weak or no activity. Telomerase activity was shown to be a good marker for early tumor diagnosis because significant telomerase activity was detected in very early tumors or even in some precancerous tissues compared with adjacent normal tissues. Telomere/telomerase is a candidate target for cancer chemotherapeutics, and an agent that abrogated telomere functions was found to kill tumor cells effectively by inducing apoptosis whereas it showed no effect on the viability of normal cells.

Recent studies have shown that pluriponten stem cells are also found in adult tissue. These adult stem cells has a great advantage over other stem cells sources, human embryos or human fetal tissue, that trouble many people on ethical grounds. While the adult stem cells have great potential for use in the cell therapy, we must pass numerous technical hurdles to reach a goal. Here we describe a subset of problems encountered in isolation and expansion of somatic stem cells for clinical application. As it is necessary to obtain the enough number of cells to supply the defect tissue and organ, we required purification and ex vivo expansion of stem cells, overcoming senescence. We also refer to the argument about plasticity of adult stem cells.

Telomerase is an enzyme that replaces repetitive (TTAGGG)n sequences on the ends of chromosomes that would otherwise be lost during successive cell divisions. Telomerase activity is closely linked to attainment of cellular immortality, a step in carcinogenesis, while lack of such activity contributes to cellular senescence. Telomerase is activated in more than 85% of malignant tumors. However, with the exception of some self-renewing tissues with high regenerative potential, telomerase activity is usually repressed in normal somatic tissues. Based on these reports, we investigated telomerase activity in gastric mucosal tissues. Telomerase activity is highest in cancer, followed by intestinal metaplasia, chronic gastritis, and normal mucosa. In patients with intestinal-type gastric cancer, telomerase activity was higher in those with intestinal metaplasia and H. pylori infection than in patients without infection. Our results suggest that H. pylori infection may influence telomerase activity in cancer and noncancerous tissue. Genes encoding three major components of human telomerase have been recently cloned. They included those for human telomerase RNA component (hTR), human telomerase reverse transcriptase (hTERT), and telomerase-associated protein 1 (TEP1). More recently, two human telomeric repeat binding factors (TRFs) have also been cloned: TRF1, considered to inhibit the action of telomerase at the telomeric region, and TRF2, believed to prevent fusion of chromosome ends and, in vitro, to remodel linear telomeric DNA into large duplex loops. However, the details of mechanisms regulating telomerase activity are still poorly understood, and specific components or binding proteins that might represent suitable targets for cancer gene therapy have not yet been identified. Therefore, we established quantitative assays using a TaqMan RT-PCR for mRNAs encoding the telomerase components hTR, hTERT, and TEP1, as well as for those encoding TRF1 and TRF2. By using our quantitative assays, we found the following results: 1) Expression of TRF1 and TRF2 mRNA was greater in the normal cells than in human malignant hematopoietic cell lines or in patients with acute leukemia, 2) hTERT mRNA expression showed changes paralleling telomerase activity and became undetectable with HL60 cell differentiation, 3) initially low expression of TRF1 and TRF2 mRNA increased during differentiation. Our results suggest that not only hTERT but also TRF1 and 2 are important regulators of telomerase activity.

Telomerase is a ribonucleprotein enzyme that extends telomeric repeats at the end of chromosome DNA. Telomere maintenance by telomerase leads to cellular immortality and carcinogenesis. Telomerase is activated in most malignant tumors while it is usually repressed in normal somati tissues, and telomerase activation is thought to be a critical step for cancer progression. These findings suggest that telomerase is a good target for cancer gene therapy. A variety of molecular technique have been used to inhibit telomerase activity in cancer cells. In this review, I introduce the representative methods which efficently inhibit telomerase activity and may have a potential for clinical application.