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Senescent Cells as Drivers of Age-Related Diseases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cielo Mae D. Marquez, Michael C. Velarde
Due to the enhanced healthy life span observed in mice after elimination of senescent cells, subsequent experiments have been undertaken to develop small molecule drugs that could mimic the same effects in human [166,167,242]. Senolytics are a new class of drugs that selectively target senescent cells for clearance. Senescent cells show a marked increase in pro-survival genes, responsible for resistance to apoptosis [243]. Transcript analysis reveals the identities of several upregulated pro-survival genes, which include ephrins (EFNB1), p21, PI3Kγ, BCL-xL, and plasminogen-activated inhibitor-2.
Nanotechnology-Mediated Radiation Therapy
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Hayflick and Moorhead coined the term “senescence” to define the lifetime capacity of cellular proliferation as a consequence of telomere shortening. Senescent cells though cease to proliferate and synthesize DNA, but remain viable, metabolically active, enlarged in size, and increased granularity with flattened shape [71, 72]. DNA damage is notably triggered in radiation-induced senescent cells followed by the p53 and pRb pathways activation to initiate cell-cycle arrest in addition to oxidative stress that drives the irradiated cells to die by apoptosis [73–75]. One of the prolific markers present in the perinuclear region of senescent cells is the senescence-associated β-galactosidase of lysosomal compartments along with surrogate markers involved in the DNA damage response (DDR) process. If the DNA damage is not repaired in the cell cycle process upon receiving a signal from the DDR, then the cell typically undergoes p53-dependent (apoptotic) or p53-independent (mitotic catastrophe) cell death. Sometimes the cells activate a chronic state of DDR signaling that leads to activation of senescence [46, 76]. These cells are also known to secrete senescence-associated secretory phenotype (SASP) pro-inflammatory factors known to modulate tumorigenic potential/inhibit tumorigenesis, proliferation, metastatic process, and immunosuppression. Senescent cells are often generated as a result of the therapy-induced consequences in a cancer patient, which in the long run might contribute to certain age-related side effects in treated cancer patients [77]. Henceforth, SASP inhibition or senolysis that targeted the elimination of senescent cells is a complementary strategy to mitigate the unwanted negative effects of radiation-based cancer therapies [78]. A few examples of inhibitors involved in the senolytic process that have been investigated in recent years are navitoclax (ABT-263) [79], obatoclax [80], and panobinostat [81], which demonstrate to kill senescence-like cells in breast cancer cells, triple-negative breast cancer cells, and NSCLC cells, respectively.
Advancements in the use of Auger electrons in science and medicine during the period 2015–2019
Published in International Journal of Radiation Biology, 2023
While the focus of Auger therapies has been largely focused on cancer, the capacity of Auger electron emitters to irradiate specific molecular sites can be used by other scientific fields. Kurt Hofer suggested that Auger electron emitters may be used to study aging (Hofer 1992). Recently, senolytic agents are being used in an attempt to reduce the adverse effects of aging and prevent recurrence of cancer in patients that have undergone therapy (Kirkland et al. 2017; Saleh et al. 2020). Auger electron emitters may be the perfect payload for such agents because of their short-range and high-LET radiotoxicity. They may also offer some level of safety over alpha particle emitters which are potent carcinogens. In another arena, Panyutin et al. considered Auger electron emitters for gene therapy (Panyutin and Neumann 1994; Panyutin et al. 2000). In these instances where deft implementation of site-specific irradiation is needed, radionuclides that decay by EC directly to the daughter ground state may be most suitable. These radionuclides emit only Auger electrons and low yields of characteristic X-rays. There are few such radionuclides with suitable physical half-lives, perhaps 71Ge may be ideal with a half-life of 11.4 days. Therefore, there remains a rich future to study DNA repair of site-specific radiation damage.
Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches
Published in Expert Review of Anticancer Therapy, 2022
Teodora Alexa-Stratulat, Mariana Pavel-Tanasa, Vlad-Andrei Cianga, Sabina Antoniu
Heat shock proteins (HSP90) are cellular components which are involved in repair and regeneration processes of the tissues. They can increase pathologically with age or in various conditions such as cancers, for the latter category their therapeutic inhibition being currently under investigation. The problem is that such ‘generic’ inhibitors can exhibit cytotoxic effects on normal cells and therefore, more recently, organelle-specific (e.g. mithocondrial or endoplasmatic reticulum) HSP90 inhibitors were developed and tested as senolytic drugs [137]. In fact, in a recent experimental study, several such HSP90 inhibitors were tested in in vitro and in vivo models of progeroid- like cellular/animal phenotypes. Geldanamycin and 17-AAG (tanespymicin) respectively 17 DMAG were found to exert senolytic effects [138]. Such senolytic effects are actually those which might prompt further clinical testing of this class in the future, because its efficacy in cancers in general and in lung cancer in particular as cytotoxic agents and stand-alone therapy are still questionable.
Identifying the challenges for successful pharmacotherapeutic management of sarcopenia
Published in Expert Opinion on Pharmacotherapy, 2022
In the case of testosterone, co-administration with finasteride, a type II 5α-reductase inhibitor, increased muscle strength and bone mineral density without causing prostate enlargement [25]. In non-hypogonadal healthy 65–75-year-old men, short-term (six week) administration of testosterone in addition to resistance exercise training, enhanced muscle mass, and performance, compared to men who did the same exercise but received a placebo treatment [26]. No adverse effects were reported with short-term treatment. The authors suggested that older women might also benefit given the similar link between declining testosterone and muscle aging in women, but reiterated that older adults receiving testosterone therapy should be carefully monitored because of potential health risks [26]. Senolytics targeting senescent cells hold much promise for their therapeutic benefits, but side effects have been identified in some studies, including potential mitochondrial impairments [27] and potential cardiotoxity [28].