Differentiating agents regulate cathepsin B gene expression in HL‐60 cells

We utilized HL‐60 cells as a model system to examine the regulation of ctsb gene expression by differentiating agents. Inducers of monocytic differentiation [phorbol ester (PMA), calcitriol (D3), and sodium butyrate (NaB)] and inducers of granulocytic differentiation [all‐trans retinoic acid (RA) and 9‐cis retinoic acid (9‐cis RA)] increase ctsb mRNA levels in a dose‐dependent manner as determined by Northern blot hybridization. D3 and retinoids exert additive effects, suggesting that these agents act in part through distinct pathways. Actinomycin D decay experiments indicate that D3, NaB, RA, and 9‐cis RA do not alter mRNA stability. In contrast, PMA markedly increases the half‐life of ctsb mRNA. In transient transfection assays, PMA and NaB both stimulate transcription of the luciferase reporter gene placed under the control of ctsb promoter fragments. Thus, inducers of HL‐60 cell differentiation can regulate the expression of the ctsb gene at both transcriptional and posttranscriptional levels. J. Leukoc. Biol. 66: 609–616; 1999.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142263/1/jlb0609.pd

Cell and Molecular Aging

Discussions of aging invariably begin by establishing a satisfactory definition for the term aging and the related word senescence. Although the term aging is commonly used to refer to postmaturational processes that lead to diminished homeostasis and increased organismic vulnerability, the more correct term for this is senescence (derived from the Latin word “senescere,” meaning to grow old or to diminish), which explicitly refers to the process of growing old and sustaining related deterioration. Aging on the other hand can refer to any time-related process. We will use senescence to refer to cellular phenomena and aging to refer to changes, as organisms grow old

Cellular and Molecular Aging

As a clinical researcher whose area of expertise is Geriatric Pelvic Medicine, the physical changes that go along with increasing age is incredibly interesting to me. However, from a more practical perspective, the biology of aging, although fascinating, is not something that I would be pushed to address in a routine clinical or administrative situation. All that notwithstanding, questions, presumptions, and theories surrounding the definition of aging are inescapable. In fact, more often than I like to admit, I will find myself getting side tracked and drifting off into deep thought about what “aging really means,” or what patients do I consider “old”? Are they really “old”? Which ones might I consider “young” and compare my assessments to their actual chronological age in years? Perhaps, the most frustrating piece of all, is that, almost invariably, after I come out of my intensely contemplative trance on” “aging,” that I end up with more questions than answers

Emerging therapies to treat frailty syndrome in the elderly

Frailty syndrome (FS) has become increasingly recognized as a major predictor of co-morbidities and mortality in older individuals. Interventions with the potential to benefit frail elders include nutritional supplementation (vitamins D, carotenoids, creatine, dehydroepiandrosterone (DHEA), and beta-hydroxy-beta-methylbutyrate) and exercise modalities (tai chi and cobblestone walking). While these have not been explicitly tested for their impact on FS, vitamin D supplementation appears to offer significant promise in enhancing long-term health of the elderly. Exercise modalities such as tai chi and cobblestone walking, because of probable low risk and ease of participation, may also confer benefit. Additional studies are needed to investigate interventions that directly prevent, delay, and/or ameliorate frailty. Successful therapies may well involve multi-component approaches utilizing a combination of medication, nutritional supplementation, and exercise

AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells

Cathepsin K (CTSK) is a secreted protease that plays an essential role in osteoclastic bone resorption, and CTSK levels increase with osteoclast differentiation and activation, a process that is controlled by a complex physiological network of hormones and cytokines. A critical regulator of this process is receptor activator of NF-kappaB ligand (RANKL), a member of the tumor necrosis factor (TNF) superfamily of cytokines that can act via the TNF receptor activating factor (TRAF6)/AP-1 signaling pathway. However, the mechanism whereby RANKL modulates CTSK expression is not fully understood. Therefore, we investigated the regulation of CTSK expression and promoter activity in RAW 264.7 osteoclast precursor cells, which can be readily differentiated to osteoclasts upon RANKL stimulation. Western blot analysis, real-time RT-PCR and luciferase reporter gene assays revealed that RANKL stimulated CTSK expression and promoter activity in a dose- and time-dependent manner and that this activation was inhibited by either dominant negative (DN) TRAF6 or DN-c-fos. TRAF6 stimulated the basal activity of a truncated CTSK promoter, and DN-c-fos blocked this stimulation. JunB alone also stimulated basal CTSK promoter activity, whereas c-jun, JunD or c-fos alone did not. However, co-transfection of any of these jun-family members with c-fos (AP-1) significantly increased CTSK promoter expression. siRNA targeted against c-jun or junB suppressed RANKL-mediated CTSK expression. Therefore, both TRAF6 and AP-1 help regulate the basal and RANKL-mediated stimulation of CTSK gene expression in RAW 264.7 cells

Vitamin D supplementation in older persons: benefits and requirements

The high prevalence of vitamin D deficiency and insufficiency in the elderly population worldwide raises concerns regarding the potential multiple health consequences of persistent, long-term, low vitamin D levels, beyond the traditional detrimental effects on calcium metabolism and bone health. Observational studies and recent randomized clinical trials have found an increased risk of falls, physical dysmobility and cancer in individuals with lower vitamin D concentrations. Cross-sectional studies have also found an inverse correlation between vitamin D levels and diabetes, cardiovascular disease and death. The optimal serum vitamin D concentration for bone health appears to have been established but the current recommended doses of vitamin D are too low to result in normal serum levels in the majority of the population and the elderly in particular. Furthermore, observational studies suggest that higher serum levels might be necessary when targeting other health outcomes