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Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions., Competing Interests: Declaration of Interests J.-P.L. is the founder of Hangzhou Duanli Biotechnology Company Limited, Hangzhou, Zhejiang, China., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Premature aging occurs frequently to various tissues and organs resulting in the tissue-specific chronic diseases. The mechanisms of tissue-specific premature aging are largely unknown. In response to environmental cues, aging may originate from cytoplasm or the nucleus of a cell with cytoplasm aging in association with organelle degeneration in terminally differentiated cells and nuclear aging with dysfunctional telomeres and irreversible cell cycle arrest in stem and cancer cells. Either cytoplasm aging or nuclear aging may cause extracellular senescence-associated low-grade inflammation to spread aging. Referring to the recent findings in this special issue of Healthy Aging in CEPP and beyond, we describe the molecular and cellular mechanisms of physiological aging and tissue-specific pathological aging in chronic diseases., (© 2017 John Wiley & Sons Australia, Ltd.)

The mini-review stemmed from a recent meeting on national aging research strategies in China discusses the components and challenges of aging research in China. Highlighted are the major efforts of a number of research teams, funding situations and outstanding examples of recent major research achievements. Finally, authors discuss potential targets and strategies of aging research in China.

Human and other multicellular life species age, and ageing processes become dominant during the late phase of life. Recent studies challenge this dogma, suggesting that ageing does not occur in some animal species. In mammals, cell replicative senescence occurs as early as before birth (i.e. in embryos) under physiological conditions. How the molecular machinery operates and why ageing cells dominate under some circumstances are intriguing questions. Recent studies show that cell ageing involves extensive cellular remodelling, including telomere attrition, heterochromatin formation, endoplasmic reticulum stress, mitochondrial disorders and lysosome processing organelles and chromatins. This article provides an update on the molecular mechanisms underlying the ageing of various cell types, the newly described developmental and programmed replicative senescence and the critical roles of cellular organelles and effectors in Parkinson's disease, diabetes, hypertension and dyskeratosis congenita., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background: Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected individuals on cART via inhibition of telomerase activity., Methods: Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART., Results: Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 μM. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47; P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11; P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01)., Conclusions: NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected individuals on cART.

The process of aging is mitigated by the maintenance and repair of chromosome ends (telomeres), resulting in extended lifespan. This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase (TERT), which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy. Underpinning increased cell proliferation, telomerase is also a key factor in facilitating cancer cell immortalization. The review focuses on aspects of hormonal regulations of telomerase, and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels. In addition, the basic structure and function of two key telomerase enzyme components-the catalytic subunit TERT and the template RNA (TERC) are discussed briefly.

Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.

1. Oestrogen plays an important role in ageing and ageing-related development. Lack of oestrogen prompts endocrine cell ageing of the ovary, whereas oestrogen overflow impacts on epithelial cell neoplastic development. 2. Recent studies indicate that oestrogen regulates cell proliferative fates by a mechanism of reprogramming the size of telomeres (ends of chromosomes) in the oestrogen target cells. This is achieved by upregulating the telomerase reverse transcriptase (TERT) gene in a temporal and spatial manner. 3. Currently, the relationship between oestrogen and telomerase activity in regulating productive cell development and function remains elusive. A number of lines of evidence suggest that telomerase is a downstream target of oestrogen in oestrogen-dependent reproductive ageing and neoplastic development. 4. The present minireview discusses our current understanding of the mechanisms by which telomerase maintenance of telomere homeostasis mediates oestrogen-induced ageing and tumourigenesis in the ovary under physiological and pathological conditions.

Estrogen regulates tissue development, function, and aging by regulating expression of critical genes. Recent studies suggest that estrogen promotes cell proliferation by stimulating telomerase activity, an enzyme that plays a key role in extending cell life span. In some estrogen-responsive tissues, estrogen appears important in regulating telomerase activity in vivo. Further characterization will provide a greater understanding of the link between estrogen, telomerase, and aging.

Telomerase is a specialised reverse transcriptase that synthesises and preserves telomeres (the ends of chromosomes), thereby playing a key role in regulating the lifespan of cell proliferation. Telomerase activity is critically involved in cell development, ageing and tumourigenesis. Activation of telomerase to maintain telomeres is required for self renewal and proliferative expansion of a number of cell types, including stem cells, activated lymphocytes and cancerous cells. However, recent studies show that the safeguard mechanisms and the modes of regulation of telomerase are more revealing than thought under various physiological and pathological conditions. Considerable evidence suggests that hormones and growth factors are crucially involved in regulating telomerase activity and gene expression of telomerase reverse transcriptase (TERT). This review briefly summarises our current understanding of how hormones and growth factors regulate the telomerase and telomere network and how deregulation can induce ageing and related diseases such as cancer.

Telomerase maintains telomeres to preclude cell senescence. It remains elusive how telomerase activity is repressed in differentiated cells, but retained at high levels in stem cells and cancer. Recent studies suggest that the Ets transcription factor family, downstream of the mitogen signaling pathways of MAP kinase, regulates telomerase activity at the gene transcription level of human telomerase reverse transcriptase (hTERT). Several Ets transcription factors are involved in regulating hTERT gene expression, both directly and indirectly through the proto-oncogene c-myc. ER81 may mediate telomerase activation in telomerase-negative fibroblasts stimulated by oncogenes Her2/Neu, Ras, and Raf. Ets2 may also play an important role in regulating the hTERT gene; but further studies are required to decipher the mechanisms in the regulation of telomerase activity. [ABSTRACT FROM AUTHOR]

Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in TERC KO mice. TERC KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the Trp53−/− allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated AEC1) in AEC2 of the late generation of TERC KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF. [ABSTRACT FROM AUTHOR]